ES2935392T3 - Imidazopyrrolopyridine as inhibitors of the JAK family of kinases - Google Patents

Abstract

2-((1r,4r)-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods of treating JAK-mediated disease states, disorders and conditions, such as inflammatory bowel disease. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Imidazopyrrolopyridine as inhibitors of the JAK family of kinases

FIELD OF THE INVENTION

[0001] The present invention relates to certain imidazopyrrolopyridine compounds. Pharmaceutical compositions containing them, methods of making them, and methods of using them as JAK inhibitors and for the treatment of JAK-mediated disease states, disorders and conditions are also disclosed.

BACKGROUND

[0002] Internal factors, external factors, or a combination of both factors can trigger or be associated with the development of abnormal immune responses in the body. Accordingly, pathological states develop in which constituents, such as substances and tissues, that are normally present in the body are subject to such an immune response. These states are generically called diseases of the immune system. Because the body's immune system is involved and the damage affects body tissue, these diseases are also known as autoimmune diseases. Because the immune system and tissue are part of the same body, the terms "autoimmune disease" and "immune system disease" are used interchangeably here, regardless of what triggers the abnormal immune system response. Furthermore, the identity or mechanism of the underlying immune problem is not always clear. See, eg, DJ Marks, et al., Crohn's disease: An immune deficiency state, Clinical Reviews in Allergy and Immunology 38(1), 20-31 (2010); JD Lalande, et al, Mycobacteria in Crohn's disease: How innate immune deficiency may result in chronic inflammation, Expert Reviews of Clinical Immunology 6(4), 633-41 (2010); JK Yamamoto-Furusho, et al., Crohn's disease: Innate immunodeficiency, World Journal of Gastroenterology, 12(42), 6751-55 (2006). As used herein, the term "autoimmune disease" does not exclude conditions whose causes include external factors or agents, such as environmental or bacterial factors, and internal factors such as genetic susceptibility. Accordingly, a condition such as Crohn's disease (CD) is referred to herein as an autoimmune disease, regardless of whether it is caused by the body itself or by external factors. See e.g. eg, JL Casanova, et al., Revisiting Crohn's disease as a primary immunodeficiency of macrophages, J. Exp. Med. 206(9), 1839-43 (2009).

[0003] Among the various adverse effects caused by autoimmune diseases, at least one of the following is typically observed: Damage and sometimes destruction of tissues and organ disruption that can affect organ growth and function. Examples of autoimmune diseases affect most major organs, endocrine and exocrine glands, blood and muscles, and a plurality of systems, such as the digestive, vascular, connective, and nervous systems. Immunosuppressive treatments are often adopted to treat autoimmune diseases.

[0004] Multiple theories are known to explain how autoimmune diseases arise, some focusing on endogenous factors and others including exogenous factors as well. At the molecular level, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is considered to play an important role in the transmission of extracellular chemical signal information to the cell nucleus, resulting in the regulation of genes that are involved in cell transmission. activities like immunity. Cytokines are an example of an extracellular molecule that plays an important role in cell signaling. Leukocytes, like neutrophils, are recruited by cytokines and chemokines to ultimately cause tissue damage in chronic inflammatory diseases.

[0005] The Janus kinase (JAK) family of proteins consists of 4 tyrosine kinases, JAK1, JAK2, JAK3 and TyK2, which are essential for intracellular signaling of type I and type II cytokine receptors. The term JAK refers to JAK1, JAK2, JAK3, or TyK2, or any combination thereof. Each JAK selectively associates with receptor subunits that dimerize (or multimerize) to form functional receptors. According to J.D. Clark, et al., Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases, J. Med. Chem. 57(12), 5023-38 (2014), "the activation step occurs when a cytokine binds to its receptor, which induces a multimerization (dimerization or higher-order complexes) of the receptor subunits.This causes the JAKs associated with each subunit to be close to one another, triggering a series of phosphorylation events that ultimately result in the phosphorylation and activation of signal transducers and activators of transcription (STAT) proteins. A phosphorylated STAT dimer is then translocated into the cell nucleus, where it binds to target genes that modulate its expression." Once in the nucleus, STATs regulate gene transcription for numerous mediators in the inflammatory process by binding to specific recognition sites on DNA. See, for example, J. Med. Chem.

57(12), 5023-38 (2014), cited above. There is considerable evidence demonstrating the importance of the JAK/STAT pathway in inflammatory, autoimmune, and cancer diseases. See, for example, M. Coskun, et al., Implication of JAK/STAT signaling in the pathogenesis of inflammatory intestinal disease, Pharmacological Research 76, 1-8 (2013); and J.J. O'Shea, et al., JAK and STAT in Immunity, Immunodeficiency, and Cancer, The New England Journal of Medicine 368, 161-70 (2013).

[0006] Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis (UC), are They are characterized by recurrent intestinal inflammation, alteration of the epithelial barrier and microbial dysbiosis. The excessive inflammatory response in the gastrointestinal tract is mediated by several proinflammatory cytokines including TNFa, IFN-y, IL-1, IL-2, IL-4, IL-6, IL-12, IL-13, IL-15, IL-17, IL-21, and IL-23 that exert their effects on cells of innate and adaptive immunity including T and B lymphocytes, epithelial cells, macrophages, and dendritic cells (DCs). See, eg, Pharmacological Research 76, 1-8 (2013), cited above; S. Danese, et al., JAK inhibition using tofacitinib for inflammatory bowel disease treatment: A hub for multiple inflammatory cytokines, American Journal of Physiology, Gastrointestinal and Liver Physiology 310, G155-62 (2016); and MF Neurath, Cytokines in inflammatory bowel disease, Nature Reviews Immunology 14, 329-42 (2014).

[0007] The prevention and/or control of such an excessive inflammatory response is desirable. In light of the mechanism of such a response summarized above, JAK inhibition (see illustration in FIG. 1 in the form of a jagged arrow showing a pan-JAK inhibitor targeting the JAK/STAT signaling pathway and inflammation) is intended to prevent or control excessive inflammatory response. JAK inhibitors that inhibit a plurality of said JAK proteins are referred to herein as pan-JAK inhibitors. Examples of therapeutic benefits of such prevention or control have been seen with tofacitinib, an orally bioavailable pan-JAK inhibitor approved in the United States for the treatment of rheumatoid arthritis and currently in clinical development for ulcerative colitis. In a phase 2 clinical trial, clinical efficacy was evaluated in 194 patients with moderate to severe ulcerative colitis. See, for example, W.J. Sandborn, et al., Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis, The New England Journal of Medicine 367, 616-24 (2012). Published information from this trial indicates that patients receiving twice daily doses (BIDs) of 0.5, 3, 10, and 15 mg achieved clinical response rates of 32, 48, 61, and 78%, respectively, compared with 42% observed with placebo. The secondary end point of clinical remission (Mayo score < 2) was also reported to be 13, 33, 48, and 41% compared to 10% seen with placebo. See, for example, The New England Journal of Medicine 367, 616-24 (2012), cited above. In a phase 3 clinical trial of UC, 88 of 476 patients achieved clinical remission after 8 weeks of treatment with tofacitinib (10 mg twice daily) compared to 10 of 122 patients receiving placebo treatment. See W.J. Sandborn, et al. Efficacy and safety of oral tofacitinib as induction therapy in patients with moderate-to-severe ulcerative colitis: results from 2 phase 3 randomized controlled trials, J. Crohns Colitis 10, S15-S (2016). Reports on Crohn's disease indicate that tofacitinib was also in development for the treatment of CD; however, it was reported to have been discontinued due to failure to achieve clinical efficacy in a 4-week/Phase 2 clinical trial for moderate to severe CD. See W.J. Sandborn, et al., A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease, Clinical gastroenterology and hepatology: The official clinical practice journal of the American Gastroenterological Association 12, 1485-93 e2 (2014). Based on the publicly reviewed literature, it is currently unclear whether the failure of tofacitinib in CD is related to clinical study design, mechanistic differences between UC and CD, or dose-limiting systemic adverse events. See Pharmacological Research 76, 1-8 (2013), cited above; Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12, 1485-93 e2 (2014), cited above; and C.J. Menet, et al., Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634, J. Med. Chem. 57, 9323-42 (2014). In light of the characteristics of this JAK inhibitor, it is desirable to find additional JAK inhibitors for the prevention and/or control of the excessive inflammatory response.

[0008] Systemic adverse events have been reported in connection with phase 2 and phase 3 inflammatory bowel disease (IBD) clinical trials with tofacitinib. See The New England Journal of Medicine 367, 616-24 (2012), cited above; Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12, 1485-93 e2 (2014), cited above; and J. Panes, et al. Efficacy and safety of oral tofacitinib for induction therapy in patients with moderate-to-severe Crohn's disease: results of a Phase 2b randomized placebo-controlled trial, J. Crohns Colitis 10, S18-S19 (2016). These adverse events include decreased absolute neutrophil counts (ANCs), elevated total cholesterol (low- and high-density lipids), intestinal perforation, and infection. Such adverse events are consistent with those observed after tofacitinib treatment in patients with rheumatoid arthritis (RA) (see, for example, J.M. Kremer, et al. Phase IIa blinded, placebo-controlled, three-dose-level trial of CP-690,550 versus placebo, Arthritis and Rheumatism 60, 1895-905 (2009)), some of which likely result from JAK2-dependent inhibition of EPO, TPO, and colony-stimulating factors (csf-2 and GM-CSF of granulocytes and macrophages)) and/or JAK1-dependent inhibition of IL-6. See, Arthritis and Rheumatism 60, 1895-905 (2009), cited above; and OH Nielsen, et al., Will novel oral formulations change the management of inflammatory bowel disease? Expert opinion on investigational drugs 25, 709-18 (2016).

[0009] Referring to Fig. 1, an orally administered drug can, in principle, follow the gastrointestinal tract from the mouth to the esophagus (1), the stomach (2) through the duodenum (3) to the jejunum (4), then to the ileum (5), and then to the colon (6). The relative absorptive areas for these various parts are approximately 60% for the jejunum (4), approximately 26% for the ileum (5), and approximately 13% for the colon (6). Absorption through these various gastrointestinal regions may cause the initiation of systemic distribution which, in turn, could cause undesirable side effects. The gastrointestinal tract has a very large surface area. See, for example, HF Helander, et al., Surface area of the digestive tract - revisited, Scandinavian Journal of Gastroenterology 49(6), 681-89 (2014); and KJ Filipski, et al., Intestinal Targeting of Drugs: Rational Design Approaches and Challenges Current Topics in Medicinal Chemistry 13, 776-802 (2013). Such a large absorption surface favors the systemic distribution of substances that can cross the walls of the various parts of the intestinal tract and reach the torrent. and, in turn, have the potential to cause unwanted side effects of a systemically distributed substance. Systemic distribution is represented by broken line arrows in FIG. 1 as permeating through the walls of the colon for simplified illustrative purposes, but such distribution is not limited to the walls of the colon, as it can also occur through the walls of other parts of the gastrointestinal tract shown in FIG. . 1, like those of the small intestine. It is also understood that the dashed arrow lines in FIG. 1 represent systemic distribution beyond the gastrointestinal tract, since it is known that such systemic distribution occurs with reference to the physiology of the gastrointestinal tract, and that such dashed arrows simply refer in a schematic illustrative manner to such systemic distribution. See, eg, Current Topics in Medicinal Chemistry 13, 777-80 (2013), cited above, for a description of intestinal tissue, transport through it, and metabolism.

[0010] One of the main reasons for dropout in drug candidates is safety and tolerability. See, for example, I. Kola, et al., Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug discovery 3, 711 5 (2004); M.J. Waring, et al., An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nature Reviews Drug Discovery 14, 475-86 (2015); M. Hay, et al., Clinical development success rates for investigational drugs, Nature Biotechnology 32, 40-51 (2014); and I. Bunnage, Getting pharmaceutical R&D back on target, Nature Chemical Biology 7, 335-9 (2011). Increasing local tissue concentrations of the compound in the intended target tissue, while limiting exposure to other tissues, may reduce unwanted side effects. See, for example, V.P. Torchilin, Drug targeting. European Journal of Pharmaceutical Sciences: Official Journal of the European Federation for Pharmaceutical Sciences11 Suppl 2, S81-91 (2000). This concept has been widely accepted for certain diseases and tissues, such as the eye (see, for example, R. Gaudana, et al., Ocular drug delivery, The AAPS Journal 12, 348-60 (2010)), skin (see, e.g., R. Folster-Holst, et al., Topical hydrocortisone 17-butyrate 21-propionate in the treatment of inflammatory skin diseases: pharmacological data, clinical efficacy, safety and calculation of the therapeutic index, Die Pharmazie 71, 115-21 (2016)) and lung (see, for example, J.S. Patil, et al., Pulmonary drug delivery strategies: A concise, systematic review, Lung India: official organ of Indian Chest Society 29, 44-9 (2012)). Similar to these tissue-directed approaches, increasing intestinal drug concentrations while limiting unwanted drug levels in other tissues may increase safety margins. See, for example, I.R. Wilding et al., Targeting of drugs and vaccines to the gut, Pharmacology & Therapeutics 62, 97 124 (1994); D. Charmot, Non-systemic drugs: a critical review, Current Pharmaceutical Design 18, 1434-45 (2012); and Current Topics in Medicinal Chemistry 13, at 780 (2013), cited above. Selective modulation of target tissues in gastrointestinal tissue with compounds that achieve limited systemic exposures can potentially improve the therapeutic index of such compounds for the treatment of diseases of the gastrointestinal tract, including ulcerative colitis and Crohn's disease. See, for example, O. Wolk, et al., New targeting strategies in drug therapy of inflammatory bowel disease: mechanistic approaches and opportunities, Expert Opin. Drug Deliv. 10(9), 1275-86 (2013). The term "systemic effects" is used here to refer to systemic exposure and the effects of any systemic exposure, although they are not always the same.

[0011] Because some known JAK inhibitors have adverse effects associated with their systemic effects, it is desirable to find new JAK inhibitors as active substances for the prevention and/or control of excessive inflammatory response and whose systemic effects are eliminated or reduced. . Furthermore, it is desirable to find JAK inhibitors with local effects on gastrointestinal tissues for the treatment of conditions such as, but not limited to, IBD, with reduced systemic effects. Due to the role played by the various JAK proteins, it is further desirable to find inhibitors of pan-JAK.

[0012] In principle, targeting to intestinal tissue can be pursued according to multiple strategies. See, for example, Current Topics in Medicinal Chemistry 13, at 780-95 (2013), cited above, which refers to approaches including physicochemical property approaches, transport-mediated approaches, prodrug approaches, and formulation and technology approaches. It is recognized, however, that "there are a number of challenges and dangers that are endemic to tissue-directed programs" and in particular to intestinal-targeted compounds, as described in Current Topics in Medicinal Chemistry 13, at 795 (2013) , cited above.

[0013] IBD conditions can spread to multiple parts of the gastrointestinal tract. Although for simplified illustrative purposes only one site of colonic disease (10) in the descending colon is shown in Fig. 1, inflammatory bowel disease can affect any part of the gastrointestinal tract such as Crohn's disease, or in the rectum and colon., as with ulcerative colitis. See, for example, NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services, <http://spotidoc.com/doc/71780/crohns-disease --national-digestive-diseases-information>, accessed 29 November 2016. IBD disease sites can be, for example, (located in the ileum), ileocolic (involving parts of the ileum and colon) and colonic (located in the colon, as illustratively shown in the descending colon in FIG. 1).Therefore, in certain disease settings, drug delivery throughout the entire or a large portion of the colon may be desirable. of the intestinal tract.In other disease settings, it may be desirable to increase the concentration in any given portion of the gastrointestinal tract.In still other settings, a combination of these two forms of administration at different sites in the intestinal tract might be desirable. final.

[0014] One such scenario would focus on the administration of an active substance that has systemic effects limited due to limited absorption when passing through the gastrointestinal tract as exemplified by the solid arrows in FIG. 1, while being available to act in large portions of the gastrointestinal (GI) tract, a feature referred to herein as "local GI effects". Due to reduced systemic effects, a wider range of doses could be evaluated for this substance. It would further be desirable for said active substance to have a low permeability so that only a small amount passes through the intestinal wall into the bloodstream to limit undesirable adverse side effects when it reaches non-target areas. In addition, JAK inhibitors are contemplated as treatment candidates for other diseases. They are intended for use in the treatment of eye conditions, including dry eye (Colligris, B., et al., Recent developments on dry eye disease treatment compound, Saudi J. Ophthalmol. 28(1), 19-30 (2014 )), myeloproliferative neoplasms, myeloproliferative diseases (EJ Baxter, et al., Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders, Lancet 365, 1054-1061 (2005); C. James, et al., A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera, Nature 434, 1144-1148 (2005), R. Kralovics, et al., A gain-offunction mutation of JAK2 in myeloproliferative disorders, N. Engl. J. Med. 352, 1779- 1790 (2005), RL Levine, et al., Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis, Cancer Cell 7, 387-397 (2005), G. Wernig, et al. , Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F induced po lycythemia vera, Cancer Cell 13, 311-320 (2008)), myeloproliferative syndrome, acute myeloid leukemia, systemic inflammatory response syndrome, systemic-onset juvenile rheumatoid arthritis, juvenile idiopathic arthritis (HW Li, et al., Effect of miR- 19a and miR-21 on the JAK/STAT signaling pathway in the peripheral blood mononuclear cells of patients with systemic juvenile idiopathic arthritis, Exp. Ther. Med. 11 (6), 2531 -2536 (2016)), type III hypersensitivity reactions, type IV hypersensitivity, inflammation of the aorta, iridocyclitis/uveitis/optic neuritis, juvenile spinal muscular atrophy, diabetic retinopathy, diabetic nephropathy, including diabetic nephropathy (FC Brosius, et al., JAK inhibition in the treatment of diabetic kidney disease, Diabetologia 59(8), 1624-7, (2016); CC Berthier, et al., Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy, Diabetes 58(2), 469-77, (2009), EN Gurzov, et al., The JAK/STAT pathway in obesity and diabetes, FEBS J. 283(16) , 3002-15 (2016)), microangiopathy, inflammation (M. Kopf, et al., Averting inflammation by targeting the cytokine environment, Nature Reviews Drug Discovery 9, 703-718 (2010); JJ O'Shea, et al. , A new modality for immunosuppression: targeting the JAK/STAT pathway, Nature Rev. Drug Discov. 3, 555-564 (2004)) chronic inflammation, disease Inflammatory bowel disease disease including ulcerative colitis (UC) and Crohn's disease (RH Duerr, et al., A genome-wide association study identifies IL23R as an inflammatory bowel disease gene, Science 314, 1461-1463 (2006); M. Coskun, et al., Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease, Pharmacol. Res. 76, 1-8 (2013); MJ Waldner, et al., Master regulator of intestinal disease: IL-6 in chronic inflammation and cancer development, Semin. Immunol. 26(1), 75-9 (2014); S. Danese, et al., JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines, Am. J. Physiol. Gastrointest. Liver Physiol. 310(3), G155-62 (2016); W. Strober, et al., Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases, Gastroenterology 140, 1756-1767 (2011)), allergic diseases, vitiligo, atopic dermatitis (R. Bissonnette, et al., Topical tofacitinib for atopic dermatitis : a phase IIa randomized trial, Br. J. Dermatol. 175(5), 902-911 (2016), W. Amano, et al., JAK inhibitor JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation, J Dermatol Sci 84, 258-265 (2016), T. Fukuyama, et al., Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis, J. Pharmacol. Exp. Ther. 354(3), 394-405 (2015)), alopecia areata (AK Alves de Medeiros, et al., JAK3 as an Emerging Target for Topical Treatment of Inflammatory Skin Diseases, PLoS One 11(10) (2016 ); L. Xing, et al., Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition , Nat. Med. 20(9), 1043-9 (2014)), scleroderma dermatitis, acute or chronic immune disease associated with organ transplantation (PS Changelian, et al. 878 (2003), F. Behbod, et al. Concomitant inhibition of Janus kinase 3 and calcineurin-dependent signaling pathways synergistically prolongs the survival of rat heart allografts, J. Immunol, 166, 3724-3732 (2001); S. Search, et al,. Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP690,550: a pilot study in de novo kidney allograft recipients, Am. J. Transplant, 9, 1936-1945 (2009)), psoriatic arthropathy, ulcerative colitis arthropathy, bullous disease autoimmune, autoimmune hemolytic anemia, rheumatoid arthritis (JM Kremer, et al., A randomized, doubleblind placebo-controlled trial of 3 dose levels of CP-690,550 versus placebo in the treatment of active rheumatoid arthritis, Arthritis Rheum. 54 (annual meeting abstract ), L40 (2006), W. Williams, et al, A randomized placebo-controlled study of INCB018424, a selective Janus kinase1&2 (JAK1&2) inhibitor in rheumatoid arthritis (RA), Arthritis Rheum. 58, ^s 431 (2008); N. Nishimoto, et al., Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader blinded randomized controlled trial of tocilizumab, Ann Rheum Dis 66(9), 1162-7 (2007 )), interstitial lung disease associated with rheumatoid arthritis, systemic lupus erythematosus (A. Goropevsek, et al., The Role of STAT Signaling Pathways in the Pathogenesis of Systemic Lupus Erythematosus, Clin. Rev. Allergy Immunol (prepublication online) < http://www.docguide.com/role-stat-signalingpathways-pathogenesis-systemic-lupus-erythematosus?tsid=5 > May 23, 2016, M. Kawasaki, et al ., Possible role of the JAK/STAT pathways in the regulation of T cell-interferon related genes in systemic lupus erythematosus, Lupus.

20(12), 1231-9 (2011); Y. Furumoto, et al., Tofacitinib ameliorates murine lupus and its associated vascular dysfunction, Arthritis Rheumatol., (on-line pre-publication) < https://www.ncbi.nlm.nih.gov/pubmed/27429362 > Jul 18, 2016)), systemic lupus erythematosus-associated lung disease, dermatomyositis/polymyositis-associated lung disease, asthma (K. Vale, Targeting the JAK/STAT path in the treatment of'Th2-high' severe asthma, Future Med. C Hem. 8(4), 405-19 (2016)), ankylosing spondylitis (AS) (C. Thompson, et al., Anti cytokine therapy in chronic inflammatory arthritis, Cytokine 86, 92-9 (2016)), disease AS-associated pulmonary disease, autoimmune hepatitis, autoimmune hepatitis type 1 (classic or lupoid autoimmune hepatitis), autoimmune hepatitis type 2 (anti-LKM antibody hepatitis), autoimmune-mediated hypoglycemia, psoriasis (CL Leonardi, et al., Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, doubleblind, placebo-controlled trial (PHOENIX 1), Lancet 371, 1665-1674 (2008); G. Chan, et al., Dosedependent reduction in psoriasis severity as evidence of immunosuppressive activity of an oral Jak3 inhibitor in humans, Am. J. Transplant. 6, S87 (2006); KA Papp, et al., Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b randomized placebo-controlled dose-ranging study, Br. J. Dermatol. 167, 668-677 (2012); M. Cargill, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes, Am. J. Hum. Genet. 80, 273-290 (2007)), type 1 psoriasis, type 2 psoriasis, plaque psoriasis, moderate to severe chronic plaque psoriasis, autoimmune neutropenia, spermatic autoimmunity, multiple sclerosis (all subtypes, BM Segal, et al. , Repeated subcutaneous injections of IL 12/23 p40 neutralizing antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomized, dose-ranging study, Lancet Neurol. 7, 796- 804 (2008), Z. Yan, et al., Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases, Clin Immunol (online pre-publication), accessed Oct 3, 2016, EN Benveniste, et al., Involvement of the j anus kinase/signal transducer and activator of transcription signaling pathway in multiple sclerosis and the animal model of experimental autoimmune encephalomyelitis, J. Interferon Cytokine Res. 34(8), 577-88 (2014).; Y. Liu, et al., Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis, J. Immunol. 192(1), 59-72 (2014)), acute rheumatic fever, Sjogren's syndrome, Sjogren's syndrome/disease-associated lung disease (T. Fujimura, et al., Significance of Interleukin-6/STAT Pathway for the Gene Expression of REG Ia, a New Autoantigen in Sjogren's Syndrome Patients, in Salivary Duct Epithelial Cells, Clin. Rev. Allergy Immunol. (online pre-publication) < https://www.ncbi.nlm.nih.gov/pubmed/ 27339601 > Jun 24, 2016), autoimmune thrombocytopenia, neuroinflammation, including Parkinson's disease (Z. Yan, et al., 2016 Oct 3, cited above). JAK inhibitors have been reported to have therapeutic applications in the treatment of cancer in addition to inflammatory diseases. (SJ Thomas, et al., The role of JAK/STAT signaling in the pathogenesis, prognosis and treatment of solid tumors, British J. Cancer 113, 365-71 (2015); A. Kontzias, et al., Jakinibs: A new class of kinase inhibitors in cancer and autoimmune disease, Current Opinion in Pharmacology, 12(4), 464-70 (August 2012), M. Pesu, et al., Therapeutic targeting of JANUS kinases, Immunological Reviews, 223, 132- 42 (Jun. 2008), P. Norman, Selective JAK inhibitors in development for rheumatoid arthritis, Expert Opinion on Investigational Drugs, 23(8), 1067-77 (August 2014). Furthermore, JAK inhibitors could be useful in the prevention of colorectal cancer because the reduction of inflammation in the colon could lead to the prevention of colon cancer.

BRIEF SUMMARY OF THE INVENTION

[0015] The present invention provides a compound or a pharmaceutically acceptable salt thereof, selected from:

2-Cyano-N-((1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) ethanesulfonamide;

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(pyrimidin-4 -ylmethyl)acetamide;

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(3-hydroxy -2,2-dimethylpropyl)acetamide;

N-(( 7r,4r,M-(Cyanomethyl)cyclohexyl)-2-(1 -((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-2-yl)acetamide;

2-(1 -((7r,4rM-(C¡anomethyl)cyclohex¡l)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (((1S,3R,5R,7S)-3-hydroxyadamantan-1-yl)methyl)acetamide;

N-(2-cyano-2-methylpropyl)-2-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b ]pyridin-2-yl)acetamide;

N-(4-cyanobicyclo[2,2,1]heptan-1-yl)-2-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d ]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-((3- hydroxyoxetan-3-yl)methyl)acetamide;

2-((ir,4r1-4-(2-(2-(4-morpholinopiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1( 6H)-yl)cyclohexyl)acetonitrile;

2-(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (7r,4rM-(hydroxymethyl)cyclohexyl)acetamide;

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxyethyl )acetamide;

N-((1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzimidamide; 2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-((1- hydroxycyclobutyl)methyl)acetamide;

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(pyrazin-2 -ylmethyl)acetamide;

N-((1 H-imidazol-2-yl)methyl)-2-(1-((1 r,4r)-4-(cyanomethyl)cyclohexyl1)-1,6-dihydroimidazo[4,5-d]pyrrolo [2,3-b]pyridin-2-yl)acetamide;

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-((1 R ,3R)-3-hydroxycyclobutyl)acetamide;

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(1-methyl -1 Hpyrazol-4-yl)acetamide;

2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 1 S,4S)-4-hydroxycyclohexyl)acetamide;

2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 1 s,3r,5R,7S)-3-hydroxyadamantan-1-yl)acetamide;

N-(4-(cyanomethyl)bicyclo[2,2,1]heptan-1-yl)-2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(3 -hydroxy-3-methylbutyl)acetamide;

2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(1 -isobutylpiperidin-4-yl)acetamide;

2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(1 H-pyrazol-4-yl)acetamide;

2-(1-((ir,4r,)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (4-(hydroxymethyl)benzyl)acetamide;

2-((7r,49-4-(2-(2-(4-(Hydroxymethyl)piperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1(6H)-yl)cyclohexyl)acetonitrile;

2-(1 -((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1 H-pyrazol-3-yl)acetamide;

2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 1-hydroxycyclopropyl)methyl)acetamide;

2-((7r,49-4-(2-(2-(4-(2-Hydroxypropan-2-yl)piperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1 -((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)acetamide;

N-((1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-hydroxy -3-methylbutanamide;

2-(1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2 -methoxyethyl)acetamide;

2-(1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-8-fluoro-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)- N-(2-hydroxy-2-methylpropyl)acetamide;

2- (( 7r,4r^-4-(2-(1 -(Methylsulfonyl)azetidin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile;3- cyano-N-((1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)methyl)propanamide;

3-(3-(1 -((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)azetidine-1- yl)-3-oxopropanenitrile;

2-((7r,49-4-(2-(1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

2-(8-chloro-1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)- N-(2-hydroxy-2-methylpropyl)acetamide;

2-(8-bromo-1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)- N-(2-hydroxy-2-methylpropyl)acetamide;

2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-methylacetamide; and 2-(1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-cyanophenyl)acetamide.

[0016] The present invention also provides a compound selected from

2-Cyano-N-((1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) ethanesulfonamide;

2-(1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(pyrimidin -4-ylmethyl)acetamide;

2-(1-((7r,49-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(3 -hydroxy-2,2-dimethylpropyl)acetamide;

N-(( 7r,4r,M-(Cyanomethyl)cyclohexyl)-2-(1 -((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-2-yl)acetamide;

2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( (1S,3R,5R,7S)-3-hydroxyadamantan-1-yl)methyl)acetamide;

N-(2-cyano-2-methylpropyl)-2-(1-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)acetamide;

N-(4-cyanobicyclo[2,2,1]heptan-1-yl)-2-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d ]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 3-hydroxyoxetan-3-yl)methyl)acetamide;

2-((7r,4r,M-(2-(2-(4-morpholinopiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1( 6H)-yl)cyclohexyl)acetonitrile;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( ( 1r,4r)-4- (hydroxymethyl)cyclohexyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-hydroxyethyl)acetamide;

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzimidamide ; 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1-hydroxycyclobutyl)methyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( pyrazin-2-ylmethyl)acetamide;

N-((1 H-imidazol-2-yl)methyl)-2-(1 -((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo [2,3-b]pyridin-2-yl)acetamide;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1R,3R)-3-hydroxycyclobutyl)acetamide;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1-methyl-1Hpyrazol-4-yl)acetamide;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1S,4S)-4-hydroxycyclohexyl)acetamide;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1 s,3r,5R,7S)-3-hydroxyadamantan-1-yl)acetamide;

N-(4-(cyanomethyl)bicyclo[2,2,1]heptan-1-yl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4 ,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 3-hydroxy-3-methylbutyl)acetamide;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1-isobutylpiperidin-4-yl)acetamide;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1 H-pyrazol-4-yl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(hydroxymethyl)benzyl)acetamide;

2-((1r,4r)-4-(2-(2-(4-(Hydroxymethyl)piperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b] pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1 H-pyrazol-3-yl)acetamide;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1-hydroxycyclopropyl)methyl)acetamide;

2-((1r,4f)-4-(2-(2-(4-(2-Hydroxypropan-2-yl)piperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[ 2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)acetamide;

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-hydroxy-3-methylbutanamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-methoxyethyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-8-fluoro-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide;

2-((1r,4r)-4-(2-(1-(Methylsulfonyl)azetidin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile; 3- Cyano-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)propanamide;

3-(3-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)azetidine -1-yl)-3-oxopropanenitrile;

2-((1r,4r)-4-(2-(1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)cyclohexyl)acetonitrile;

2-(8-chloro-1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide;

2-(8-bromo-1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-methylacetamide ;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-cyanophenyl)acetamide; and

pharmaceutically acceptable cocrystals thereof.

[0017] The present disclosure relates to certain imidazopyrrolopyridine compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them as JAK inhibitors and for the treatment of JAK-mediated disease states, disorders and conditions.

[0018] The present invention relates to the compounds and their pharmaceutically acceptable salts and co-crystals provided in the appended claims. Disclosed herein are compounds of Formula I and Formula II. The term "compounds of the invention" and "compound of the invention" is intended to encompass at least one compound selected from the claims, either in solvent-free form or in any of the hydrated and/or solvated forms as illustrated herein. Compounds of Formulas I and II which are not listed in the appended claims do not form part of the present invention.

[0019] The present disclosure relates to compounds, pharmaceutical compositions containing them, methods of preparing and purifying them, methods of using them as JAK inhibitors, and methods of using them in the treatment of JAK-mediated diseases, disorders, and conditions.

[0020] Embodiments of this invention exhibit pan-JAK inhibition effects with low or negligible local GI effects and systemic effects. Furthermore, embodiments of this invention with such characteristics can be administered orally.

[0021] Furthermore, a method of treating a subject suffering from or diagnosed with a JAK-mediated disease, disorder or medical condition using compounds of the invention is described.

[0022] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure.

[0023] One aspect of the disclosure is a compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein R1 is selected from the group consisting of

(to)

where

m is 0 or 1;

n is 0 or 1;

^R7 and ^R8 are independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 perhaloalkyl, C3-C10 cycloalkyl, C3-C7 heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein in each of said R ⁷ and R ⁸ , each of C1-C6 alkyl, C1-C6 perhaloalkyl, C3-C10 cycloalkyl, C3-C7 heterocyclyl, phenyl, and 5- or 6-membered heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, -OH, -CN, C1-C4 alkyl, -OC1-C6 alkyl, -OperhaloC1-C4 alkyl, phenyl, -O-pyridine, -Si(CH ³ ) ³ , -( OCH2CH2)2-NH2, -C(O)NH2, -C(OH)(CF ³ ) ² ,-(CH ² )P(O)(OCH ² CH ³ ) ² , CH2CN and CH2OH; either

R ⁷ and R ⁸ are taken together with the nitrogen to which they are attached to form a 4 to 7 membered heterocyclic ring,

wherein said 4 to 7 membered heterocyclic ring contains 1-2 heteroatoms, wherein said heteroatoms are selected from the group consisting of O, N, and S(O)p, where p is 0, 1, or 2; said 4 to 7 membered heterocyclic ring is optionally substituted with one or two substituents selected from the group consisting of OH, CN, CH2OH, -CH( ^CH3 )2OH, CH2CN, -C(O)CH3, C1-alkyl- C6, morpholino, perhaloC1-C3alkyl, phenyl, benzyl, pyridyl, fluoro and OC1-C6alkyl;

(b)

where R ⁹ is selected from the group consisting of NH, N-OH, and O; and R ¹⁰ is selected from the group consisting of C1-C6 alkyl, C3-C10 cycloalkyl, phenyl, benzyl, pyrazolyl, OC1-C6 alkyl, phenoxy, NH2, -NHCH 2 -C3-C10 cycloalkyl, -NHAC1-C6 alkyl and -NHphenyl; wherein in said R ¹⁰ , C1-C6 alkyl and phenyl are each independently optionally substituted with one or two substituents selected from the group consisting of C3-C10 cycloalkyl, piperidinyl, OH, CN and OC1-C6 alkyl;

(c)

where R ¹¹ is selected from the group consisting of phenyl, C3-C10 cycloalkyl and C1-C6 alkyl, wherein in said R ¹¹ , C1-C6 alkyl are optionally substituted with one or two substituents selected from the group consisting of OC1-alkyl C6, C3-C10 cycloalkyl and piperidinyl;

(d)

where R ¹² and R ¹³ are independently selected from the group consisting of C1-C3 alkyl and phenyl;

(e) CH2OR14,

where R ¹⁴ is selected from the group consisting of C1-C6 alkyl, -C(O)NHCH2CH2OCH 3,

(f) any cyclohexyl that is optionally substituted with Si(CH ³ ) 3 or phenyl that is optionally substituted with one or two substituents selected from the group consisting of -CN, SF5, ^-4 -SO2CH 3 -phenyl, and

where R ¹⁵ is selected from the group consisting of H, -CN, CH2OH, and -C=CH;

(g) 5- or 6-membered HR heteroaryl ring optionally containing 1-4 heteroatoms selected from the group consisting of O, N and S, said 5- or 6-membered HR heteroaryl ring being optionally substituted with one or two substituents selected from group consisting of halo, C3-C4cycloalkyl, C1- ^C6alkyl , phenyl, -CH2Oxazolyl, -CH2C(O)NHcyclopropyl, -CH2C(O)2CH2CH3, -CH2C(CH3)2OH, CN, NH2 , NHCH and SCH3;

(h) C 4 -C 7 heterocyclic ring, wherein said C 4 -C 7 heterocyclic ring is optionally substituted with one or two substituents selected from the group consisting of -CO 2 CH 2 CH 3 , -SO 2 CH 3 , -COCH 3 , CH2C(CHa) ³ , C( ^CH3 ) ³ , CH3, C(O)CH2CN, CH2C(OH)( ^CH3 ) ² and 4-CN-phenyl;

(i) -CH 2 -NR ⁴ R 5 , where R ⁴ and R ⁵ are each independently selected from the group consisting of H and SO 2 R 6 , where R ⁶ is selected from the group consisting of cyclohexyl, phenyl optionally substituted with CN and C1- ^C5 alkyl optionally substituted with CN;

(j)-CH2-A, wherein A is selected from the group consisting of

a 5-membered heteroaryl ring selected from the group consisting of thiazolyl, imidazolyl, pyrrolyl, and pyrazolyl; heterocyclic ring

wherein R15 is selected from the group consisting of phenyl, cyclopropyl, and isopropyl; and

and

(k)-(CH2) s-(OCH2CH2)qOCH 3, where s is 1 or 2, and q is 1, 2, or 3.

[0024] A further aspect of the disclosure is a compound of Formula II, or a pharmaceutically acceptable salt thereof

where s is 0 or 1, provided that

when s is 1, then X is selected from the group consisting of H, halo, and methyl;

when s is 0, then X is halo or methyl;

Y is CH3 or H; and

RASe selected from the group consisting of

BRIEF DESCRIPTION OF THE FIGURES

[0025]

Figure 1.

Schematic diagram of part of the human gastrointestinal tract, shown as a stretched representation not to scale. The duodenum (3), jejunum (4), and ileum (5) (all shown schematically) form the small intestine after the stomach (2) and esophagus (1). The large intestine comprises the colon (6), which in turn includes the cecum (7) and appendix (not shown), the ascending colon, the transverse colon, the descending colon, the sigmoid colon (loop not shown). in it) and the rectum (11). The transverse colon is the portion between the right (8) and left (9) colonic angles, the ascending colon extends from the cecum (7) to the right colonic angle (8), and the descending colon extends from the angle left colonic. (9) to the rectum (11). Various distribution patterns are illustrated with reference to the colon for convenience, but may also refer to other parts of the gastrointestinal tract. Systemic distribution is represented by broken line arrows in FIG. 1 passing through the walls of the colon for simplified illustrative purposes, but such distribution is not limited to the walls of the colon, as it can also occur through the walls of other parts of the gastrointestinal tract. is shown in FIG. 1, like those of the small intestine. The distribution with some tissue penetration is represented by solid arrows in FIG. 1 as penetrating colonic tissue for simplified illustrative purposes, but such penetration is not limited to colonic tissue, as it can also take place in tissue in other parts of the gastrointestinal tract shown in FIG. 1, as the tissue of the small intestine. The effect of an embodiment of a JAK inhibitor according to this invention is illustratively shown as a disruption of the JAK/STAT signaling pathway that would otherwise lead to inflammation associated with inflammatory bowel disease ("IBD"). ), such as Crohn's disease or ulcerative colitis. By way of example, but not limitation, a disease site is illustratively shown as a colonic disease site (10) in the descending colon.

Figure 2.

Schematic diagram showing preparation/interconversion of embodiments of compound Ex. 1.

Figure 3.

Overlay of high performance X-ray powder diffraction (HT-XRPD) patterns for the following compound embodiments e.g. 1, from bottom to top: Is, 2 (obtained by equilibration at room temperature in 1,4-dioxane), 3b (obtained by thermocycling in cyclohexanone), 1b+4 (obtained by crystallization by cooling to |jl scale from methanol/ water (50/50, v/v), 5 (obtained by thermocycling in chloroform), 6 (obtained by ml-scale cooling crystallization from acetonitrile), 7 (obtained from 1s+7, obtained in turn by solvent equilibrium in heptane), 7 (obtained by desolvation of 1s+7, obtained in turn by equilibration of the solvent in heptane), 8 (obtained by desolvation of embodiment 5 by cyclic differential scanning calorimetry) and 9 (obtained by desolvation of embodiment 2 by cyclic differential scanning calorimetry)).

Figure 4.

Overlay of high performance X-ray powder diffraction (HT-XRPD) patterns for the following embodiments of compound Ex. 1, from bottom to top: Is (starting material), 1a (obtained after exposure to accelerated aging conditions (AAC) (40 °C and 70% relative humidity) various forms of samples of embodiment 1s), 1b (obtained by equilibration with solvent at room temperature in toluene), 1c (obtained by crystallization by cooling to j l scale from ethyl acetate/1,4-dioxane (50/50, v/v)), Id (obtained by crystallization by cooling to j l scale from acetonitrile/chloroform (50/50, v/v)) , 1e (obtained by cold crystallization on a j l scale from ethyl acetate/1,4-dioxane (50/50, v/v)), If (obtained by equilibrating the solvent at room temperature in p-xylene), 1 g (obtained by equilibrating the solvent at 50 °C in anisole), 1 h (obtained by crystallization by cooling on a j l scale in p-xylene).

Figure 5.

Overlay of high-performance X-ray powder diffraction (HT-XRPD) patterns for the following embodiments of compound Ex. 1, from bottom to top: Is, 3b (obtained by thermocycling in cyclohexanone), 3c (obtained by crystallization by cooling to j l scale in 1,4-dioxane), 3d (obtained by crystallization by cooling to j l sieve in tetrahydrofuran), and 3e (obtained by thermocycling in isobutanol).

Figure 6.

HR-XRPD diffractograms of embodiment Is in its initial form ("Is"), after a four day exposure at 40°C and 70% relative humidity ("1s 70RH"), and after an exposure of four days at 25°C and 100% relative humidity ("10").

DETAILED DESCRIPTION OF THE INVENTION

[0026] As used in this document, the terms "including", "containing" and "comprising" are used in their open and non-limiting sense.

[0027] Unless specifically qualified in particular cases of use, the term "lower alkyl" or "lower alkyl" refers to a straight or branched chain alkyl group having 1 to 8 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and which in light of ordinary experience in the art and the teachings provided herein would be considered equivalent to any of the above examples. " C1-4 alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms in the chain.

[0028] The term "alkoxy" includes a straight or branched chain alkyl group with a terminal oxygen linking the alkyl group to the remainder of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, etc.

[0029] The term "aryl" refers to a monocyclic aromatic carbocycle (ring structure having ring atoms that are all carbon) having 6 ring atoms. (The carbon atoms in the aryl groups are sp ² hybridized.)

[0030] The term "phenyl" represents the following moiety:

[0031] The term "heteroaryl" refers to a monocyclic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 5 to 6 ring atoms by heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of correctly linked moieties:

[0032] A "heterocycloalkyl" refers to a monocyclic ring structure that is saturated or partially saturated and has 4 to 6 ring atoms per ring structure selected from carbon, oxygen, and nitrogen. Illustrative entities, in the form of correctly joined fractions, include:

[0033] The term "cyano" refers to the group -CN.

[0034] The term "cycloalkyl" refers to a monocyclic, fused polycyclic or spiropolycyclic saturated or partially saturated carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities, in the form of properly joined moieties:

[0035] The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.

[0036] The term "perhaloalkyl" or "haloalkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms in the chain that optionally replaces hydrogens with halogens. The term "haloC1-4alkyl", as used herein, refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms in the chain, optionally substituting halogens for hydrogens. The term "haloC1-alkyl" -6", as used herein, refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms in the chain, optionally substituting halogens for hydrogens. Examples of groups are "perhaloalkyl", "haloalkyl " include trifluoromethyl (CF3), difluoromethyl (CF 2 H), monofluoromethyl (CH 2 F), pentafluoroethyl (CF 2 CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (-CF(CF3) 2), and groups that in light of ordinary experience in the art and the teachings provided herein would be considered equivalent to any of the above examples.

[0037] Those skilled in the art will recognize that the species of heteroaryl, cycloalkyl, and heterocycloalkyl groups listed or illustrated above are not exhaustive, and that additional species may also be selected within the scope of these defined terms.

[0038] The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or is substituted by one or more substituents. When the term "substituted" is used to describe a structural system, substitution is intended to occur at any permitted valence position in the system.

[0039] Any Formula provided herein is intended to represent compounds having structures represented by the structural Formula, as well as certain variations or forms. Certain structures can exist as tautomers. In addition, an amorphous form, hydrates, solvates, polymorphs, and pseudopolymorphs of such compounds of this invention, and mixtures thereof, are also contemplated as parts of this invention.

Reference to a compound in this document means a reference to any of: (a) the actually cited form of said compound, and (b) any of the forms of said compound in the medium in which the compound is considered when named . For example, reference herein to a compound such as R-COOH encompasses reference to any of, for example, R-COOH(s), R-COOH(sol) and R-COO-(sol). In this example, R-COOH(s) refers to the solid compound, as it might be for example in a tablet or some other solid pharmaceutical composition or preparation; R-COOH (sol) refers to the undissociated form of the compound in a solvent; and R-COO-(sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether said dissociated form is derived from R-COOH, one of its salts, or from any other entity producing R-COO - after dissociation in the medium under consideration. In another example, a term such as "exposing an entity to the compound of Formula R-COOH" refers to exposing said entity to the form(s) of the compound R-COOH that exists, or exist, in the environment in which it is produced. such exposure. In yet another example, a term such as "reacting an entity with a compound of Formula R-COOH" refers to the reaction of (a) said entity in the chemically relevant form or forms of said entity existing, or existing, in the medium in which said reaction takes place, with (b) the chemically relevant form or forms of the R-COOH compound which exists or exist in the medium in which said reaction takes place. In this sense, if said entity is, for example, in an aqueous medium, it is understood that the compound R-COOH is in that same medium, and therefore the entity is exposed to species such as R-COOH (aq) and/or R- COO-(aq), where the subscript "(aq)" means "aqueous" according to its conventional meaning in chemistry and biochemistry. In these nomenclature examples a carboxylic acid function has been chosen; however, this choice is not intended to be a limitation, but merely an illustration. It is understood that analogous examples can be given in terms of other functional groups, including, but not limited to, hydroxyl, basic nitrogenous elements, such as those in amines, and any other groups that interact or are transformed in a known manner in the medium containing the product. compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis, including hydrolysis, solvation, including hydration, protonation, and deprotonation. No further examples in this regard are provided in this document because these interactions and transformations in a given medium are known to any person skilled in the art.

[0040] Any Formula provided herein is also intended to represent unlabeled as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures represented by the Formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number in an enriched form. Examples of isotopes that can be incorporated into the compounds of the invention in a way that exceeds natural abundances include isotopes of hydrogen, carbon, nitrogen, and oxygen such as 2H, 3H, 11C, 13C, 14C, 15N, 18O and 170, respectively. Such isotopically labeled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example, deuterium (i.e. D or 2 H); or tritium (i.e. T or 3 H)), detection or imaging techniques [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)], including assays for distribution of drugs or substrates in tissues, or in radioactive treatment of patients. In particular, a compound labeled with 18 F or 11 C may be particularly preferred for PET or SPECT studies. In addition, substitution with heavier isotopes such as deuterium (ie, 2H) may provide certain therapeutic advantages resulting from increased metabolic stability, eg, increased local in vivo half-life or reduced dosage requirements. The isotopically labeled compounds of this invention can generally be prepared by carrying out the procedures described in the schemes or in the examples and preparations described below, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0041] The term Cn alkyl refers to an aliphatic chain, either straight or branched, with a total number of N carbon elements in the chain satisfying n < N < m, with m > n.

[0042] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and that vary in the displacement of hydrogen atoms and electrons. Therefore, two structures that have an H element in different positions can be in equilibrium and satisfy the valence rules. For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with acids or bases.

[0043] Certain examples contain chemical structures that are represented as (Z*) or (E*). When (Z*) or (E*) is used in the name of a compound, the absolute geometry of the corresponding double bond is unknown. The compound is a pure single isomer, but the absolute configuration has not been established. Thus, a compound designated as (Z*) refers to a compound with an absolute configuration of (Z) or (E) and a compound designated as (E*) refers to a compound with an absolute configuration of (Z ) or (E). In cases where absolute geometry has been confirmed, structures are named using (Z) and (E).

[0044] The compounds of this invention may possess one or more asymmetric centers; therefore, such compounds can be produced as individual (R)- or ( S) -stereoisomers or as mixtures thereof.

[0045] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or not, thereof. Methods for determination of stereochemistry and separation of stereoisomers are well known in the art.

[0046] In another example, a zwitterionic compound is included here by referring to a compound known to form a zwitterion, even if not explicitly named in its zwitterionic form. Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compounds are IUPAC-endorsed standard names that are well known and part of standard sets of defined scientific names. In this sense, the Dictionary of Molecular Entities of Chemical Entities of Biological Interest (ChEBI) assigns the name zwitterion the name identification CHEBI:27369. As is well known, a zwitterion or zwitterionic compound is a neutral compound having formal unit charges of opposite sign. Sometimes these compounds are called "internal salts." Other sources refer to these compounds as "zipper ions", although other sources consider the latter term to be a misnomer. As a specific example, aminoethanoic acid (the amino acid glycine) has the Formula H 2 NCH ² COOH, and exists in some media (in this case neutral media) as the zwitterion H 3 NCH ² COO -. Zwitterionic ions, zwitterionic compounds, inner salts, and zwitterionic ions in the known and well-established meanings of these terms are within the scope of this invention, as will in any event be appreciated by those skilled in the art. Because there is no need to name each and every embodiment that would be recognized by those skilled in the art, no structure of the zwitterionic compounds that are associated with the compounds of this invention is explicitly provided herein. They are, however, part of the embodiments of this invention. No further examples in this regard are provided herein because the interactions and transformations in a given medium that lead to the various forms of a given compound are known to one of ordinary skill in the art.

[0047] When referring to any Formula provided herein, the selection of a particular moiety from a list of possible species for a specific variable is not intended to define the same choice of species for the variable appearing elsewhere. In other words, when a variable appears more than once, the choice of the species from a specific list is independent of the choice of the species for the same variable elsewhere in the Formula, unless otherwise stated.

[0048] As a first example on substituent terminology, if the substituent example S 1 is one of S 1 and S 2, and the substituent example S ² is one of S 3 and S 4, then these assignments refer to embodiments of this invention given according to the options S 1 example is S 1 and S ² example is S 3; S 1 example is S 1 and S ² example is S 4; S 1 example is S ² and S ² example is S 3; S 1 example is S ² and S ² example is S 4; and equivalents of each such choice. The shorter term "S 1example is, one of S 1 and S 2, and S ² example is one of S 3 and S 4", is used herein for the sake of brevity, but not by way of limitation. The first example above on substituent terminology, which is stated in generic terms, is intended to illustrate the various substituent assignments described herein.

[0049] In addition, when more than one assignment is given for any element or substituent, aspects of this disclosure include the various groupings that can be made from the listed assignments, taken independently, and their equivalents. By way of second example on substituent terminology, if exemplary substituent S is described herein as one of S 1 , S ² and S 3 , this listing refers to aspects of this disclosure for which S example is S ¹ ; S example is S ² ; S example is S ³ ; S example is one of S ¹ and S ² ; S example is one of S ¹ and S ³ ; S example is one of S ² and S ³ , S example is one of S ¹ , S ² and S ³ , and S example is any equivalent of each of these options. The shorter term "S example is one of S ¹ , S ² , and S ³ " is used in this document for the sake of brevity, but not by way of limitation. The second example above on substituent terminology, which is stated in generic terms, is intended to illustrate the various substituent assignments described herein.

[0050] The nomenclature "C ij" with j > i, when applied herein to a class of substituents, is intended to refer to aspects of this disclosure for which each and every element of carbon, from iaj including i and j, is performs independently. By way of example, the term C ^1-4 independently refers to embodiments having one carbon element (C ¹ ), embodiments having two carbon elements (C ² ), embodiments having three elements carbon (C ³ ) and embodiments having four carbon (C ⁴ ) elements.

[0051] One aspect of the disclosure is a compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein R1 is selected from the group consisting of

(to)

in which

m is 0 or 1;

n is 0 or 1;

R ⁷ and R ⁸ are independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 perhaloalkyl, C3-C10 cycloalkyl, C3-C7 heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein in each of said R ⁷ and R ⁸ , each of C1-C6 alkyl, C1-C6 perhaloalkyl, C3-C10 cycloalkyl, C3-C7 heterocyclyl, phenyl, and 5- or 6-membered heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, -OH, -CN, C1-C4 alkyl, -OC1- ^C6 alkyl, -OPerhaloC1-C4 alkyl, phenyl, -O-pyridine, -Si(CH ³ ) ³ , -(OCH2CH2)2-NH2, -C(O)NH2, -C(OH)(CF ³ ) ² ,-(CH ² )P(O) (OcH2CH3)2, CH2CN and CH2OH; _ or R ⁷ and R ⁸ are taken together with the nitrogen to which they are attached to form a 4 to 7 membered heterocyclic ring, wherein said heterocyclic ring

4 to 7 elements contains 1-2 heteroatoms, wherein said heteroatoms are selected from the group consisting of O, N, and S(O) p, where p is 0, 1, or 2; said 4 to 7 membered heterocyclic ring is optionally substituted with one or two substituents selected from the group consisting of OH, CN, CH2OH, -CH(CH3)2OH, CH2CN, -C(O) ^CH3 , C1-C6 alkyl, morpholino, perhaloC1-C3alkyl, phenyl, benzyl, pyridyl, fluoro and OC1-C6alkyl;

(b)

where R ⁹ is selected from the group consisting of NH, N-OH, and O; and R ¹⁰ is selected from the group consisting of C1-C6 alkyl, C3-C10 cycloalkyl, phenyl, benzyl, pyrazolyl, OC1-C6 alkyl, phenoxy, NH2, -NHCH2-C3-C10 cycloalkyl, -C1-C6 NHalkyl, and - NHphenyl; wherein in said R ¹⁰ , C1-C6 alkyl and phenyl are each independently optionally substituted with one or two substituents selected from the group consisting of C3-C10 cycloalkyl, piperidinyl, OH, CN and OC1-C6 alkyl;

(c)

where R ¹¹ is selected from the group consisting of phenyl, C3-C10 cycloalkyl and C1-C6 alkyl, wherein in said R ¹¹ , C1-C6 alkyl are optionally substituted with one or two substituents selected from the group consisting of OC1-alkyl ^C6 , C3-C10 cycloalkyl and piperidinyl;

(d)

where R ¹² and R ¹³ are independently selected from the group consisting of C1-C3 alkyl and phenyl;

(e) CH2OR14,

wherein R ¹⁴ is selected from the group consisting of:

C1-C6 alkyl, -C(O)NHCH ² CH ² OCH ³ ,

(f) cyclohexyl that is optionally substituted with Si(CH ³ ) ³ or phenyl that is optionally substituted with one or two substituents selected from the group consisting of -CN, SF5, -4-SO ² CH ³ -phenyl, and

where R ¹⁵ is selected from the group consisting of H, -CN, CH2OH, and -C=CH;

(g) 5- or 6-membered HR heteroaryl ring optionally containing 1-4 heteroatoms selected from the group consisting of O, N and S, said 5- or 6-membered HR heteroaryl ring being optionally substituted with one or two substituents selected from group consisting of halo, C3-C4 cycloalkyl, C1-C6 alkyl, phenyl, -CH2Oxazolyl, -CH2C(O)NHcyclopropyl, -CH ² C(O) ² CH ² CH ³ , -CH ² C(CH ³ ) ² OH, CN, NH2, NHCH3 and SCH3;

(h) C4-C7 heterocyclic ring, wherein said C4-C7 heterocyclic ring is optionally substituted with one or two substituents selected from the group consisting of -CO2CH2CH3, -SO2CH3, -COCH3, ^CH2C ( ^CH3 ) ³ , C(CH ³ ) ³ , CH3, C(O)CH2CN, CH2C(OH)(CH ³ ) ² and 4-CN-phenyl;

(i) -CH2-NR ⁴ R ⁵ , where R ⁴ and R ⁵ are each independently selected from the group consisting of H and SO2R6, where R ⁶ is selected from the group consisting of cyclohexyl, phenyl optionally substituted with CN, and C1-C5 alkyl optionally substituted with CN;

(j) -CH2-A, wherein A is selected from the group consisting of

a 5-membered heteroaryl ring selected from the group consisting of thiazolyl, imidazolyl, pyrrolyl, and pyrazolyl;

heterocyclic ring

wherein R15 is selected from the group consisting of phenyl, cyclopropyl, and isopropyl; and

and

(k) -(CH2)s -(OCH ² CH ² )qOCH ³ , where s is 1 or 2, and q is 1,2 or 3.

[0052] A further aspect of the disclosure is a compound of Formula II, or a pharmaceutically acceptable salt thereof

in which s is 0 or 1, provided that

when s is 1, then X is selected from the group consisting of H, halo, and methyl;

when s is 0, then X is halo or methyl;

Y is CH ³ or H; and

RA is selected from the group consisting of

[0053] Another aspect of the disclosure is a compound of Formula I, wherein R1 is

in which

m is 0 or 1;

n is 0 or 1;

R ⁷ and R ⁸ are independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 perhaloalkyl, C3-C10 cycloalkyl, C3-C7 heterocyclyl, phenyl, and 5- or 6-membered heteroaryl;

wherein in each of said R ⁷ and R ⁸ , each of C1-C6 alkyl, C1-C6 perhaloalkyl, C3-C10 cycloalkyl, C3-C7 heterocyclyl, phenyl and 5- or 6-membered heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, -OH, -CN, C1-C4 alkyl, -OC1-C6 alkyl, -OperhaloC1-C4 alkyl, phenyl, -O-pyridine, -Si(CH ³ ) ³ , -( OCH2CH2)2-NH2, -C(O)NH2, -C(OH)(CF ³ ) ² ,-(CH2)P(O)(OCH2CH3)2, CH2CN and CH2OH.

[0054] A further aspect of the disclosure is a compound of Formula I, wherein R1 is

in which

m is 0 or 1;

n is 0 or 1;

R ⁷ and R ⁸ are taken together with the nitrogen to which they are attached to form a 4 to 7 membered heterocyclic ring, wherein said 4 to 7 membered heterocyclic ring contains 1-2 heteroatoms, wherein said heteroatoms are selected from the group consisting of O, N, and S(O)p, where p is 0, 1, or 2;

said 4 to 7 membered heterocyclic ring is optionally substituted with one or two substituents selected from the group consisting of OH, CN, CH2OH, -CH( ^CH3 ) ^2OH , CH2CN, -C(O) ^CH3 , C1-alkyl- ^C6 , morpholino, perhaloC1-C3alkyl, phenyl, benzyl, pyridyl, fluoro, and OC1-C6alkyl.

[0055] Another aspect of the disclosure is a compound of Formula I, wherein R ¹

R9

R10N^

*H

is where R ⁹ is selected from the group consisting of NH, N-OH, and O; and

R ¹⁰ is selected from the group consisting of C1-C6 alkyl, C3-C10 cycloalkyl, phenyl, benzyl, pyrazolyl, O-C1-C6 alkyl, phenoxy, NH2, -NHCH2-C3-C10 cycloalkyl,

-NHC1-C6alkyl and -NHphenyl; wherein in said R ¹⁰ , C1-C6 alkyl and phenyl are each independently optionally substituted with one or two substituents selected from the group consisting of C3-C10 cycloalkyl, piperidinyl, OH, CN, and C1-C6 Oalkyl.

[0056] Another aspect of the disclosure is a compound of Formula I, wherein R ¹⁰ is selected from the group consisting of

[0057] Another aspect of the disclosure is a compound of Formula I, where R9 is NH or N-OH and where R10 is selected from the group consisting of

[0058] Another aspect of the disclosure is a compound of Formula I, wherein R1 is

where R ¹¹ is selected from the group consisting of phenyl, C3-C10 cycloalkyl and C1-C6 alkyl, wherein in said R ¹¹ , C1-C6 alkyl are optionally substituted with one or two substituents selected from the group consisting of Oalkyl ^C1C6 , C3-C10cycloalkyl and piperidinyl.

[0059] Another aspect of the disclosure is a compound of Formula I, wherein R ¹¹ is selected from the group consisting of

where R ¹² and R ¹³ are independently selected from the group consisting of C1-C3 alkyl and phenyl.

[0061] Another aspect of the disclosure is a compound of Formula I, wherein R1 is ^CH2OR14 , wherein R14 is selected from the group consisting of ^C1 - ^C6 alkyl, -C(O)NHCH2CH2OCH3,

[0062] Another aspect of the disclosure is a compound of Formula I, wherein R1 is cyclohexyl which is optionally substituted with Si(CH3)3 or phenyl which is optionally substituted with one or two substituents selected from the group consisting of -CN , SF ⁵ , -4-SO2CH3-phenyl, and where R15 is selected from the group consisting of H, -CN, CH ² OH, and -CeCH;

[0063] Another aspect of the disclosure is a compound of Formula I, wherein R ¹ is a 5 or 6 membered HR heteroaryl ring optionally containing 1-4 heteroatoms selected from the group consisting of O, N and S, said 5- or 6-membered heteroaryl ring HR which are optionally substituted with one or two substituents selected from the group consisting of halo, C3-C4 cycloalkyl, C1-C6 alkyl, phenyl, -CH2oxazolyl, -CH2C(O)NHcyclopropyl, - CH ² C(O) ² CH ² CH ³ , -CH ² C(CH ³ ) ² OH, CN, NH2, NHCH3, and SCH3.

[0064] Another aspect of the disclosure is a compound of Formula I, wherein R ¹ is a C4-C7 heterocyclic ring, wherein said C4-C7 heterocyclic ring is optionally substituted with one or two substituents selected from the group consisting of of -CO2CH2CH3, -SO2CH3, -COCH3, CH ² C(CH ³ ) ³ , C(CH ³ ) ³ , CH3, C(O)CH2CN, CH ² C(OH)(CH ³ ) ² and 4-CN- phenyl.

[0065] Another aspect of the disclosure is a compound of Formula I, wherein R1 is -CH ² -NR4R5, wherein R4 and R5 are each independently selected from the group consisting of H and SO ² R6, where R6 is selected from the group consisting of cyclohexyl, phenyl optionally substituted with CN, and ^C1 - ^C5 alkyl optionally substituted with CN.

[0066] Another aspect of the disclosure is a compound of Formula I, wherein R1 is -CH ² -A, wherein A is selected from the group consisting of

a 5-membered heteroaryl ring selected from the group consisting of thiazolyl, imidazolyl, pyrrolyl, and pyrazolyl;

heterocyclic ring

wherein R15 is selected from the group consisting of phenyl, cyclopropyl, and isopropyl; and

[0067] Another aspect of the disclosure is a compound of Formula I, wherein R1 is -(CH2)s-(OCH2CH2)qOCH3, wherein s is 1 or 2, and q is 1, 2, or 3.

[0068] Another aspect of the disclosure is a pharmaceutical composition for treating a disease, disorder or medical condition mediated by JAK activity, comprising an effective amount of at least one chemical entity selected from compounds of Formula I.

[0069] Another aspect of the disclosure is a compound of Formula II, wherein RA is

s is 1; Y is H; and X is Cl.

[0070] A further aspect of the disclosure is a compound of Formula II, wherein RA is

s is 1; Y is H; and X is Br.

[0071] A further aspect of the disclosure is a compound of Formula II, wherein RA is

ooh

^Cí

Y>.

s is 1; Y is H; and X is F.

[0072] Another aspect of the disclosure is a compound of Formula II, wherein Ra is

ooh

" you

and->

s is 1; Y is CH3; and X is H.

[0073] Another aspect of the disclosure is a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-hydroxy-2-methylpropyl)acetamide;

2- (( 1r,4r)-4- ( 2- ( 1H -Imidazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( cyclopropylmethyl)acetamide;

N-(2-cyanoethyl)-2-(1-((1 R,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( tetrahydro-2Hpyran-4-yl)acetamide;

2-((1r,4r)-4-(2-(2-Oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(hydroxymethyl)phenyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(ethyl)phenyl)acetamide cyanoma;

2- (( 1r,4r)-4- ( 2- ( 1 H-1 ,2,4-Triazol-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (tetrahydro-2Hpyran-4-yl)methyl)acetamide;

2-((1r,4r)-4-(2-(Oxazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

2- (( 1r,4r)-4- ( 2- ( 2H-1 ,2,3-Triazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H )-yl)cyclohexyl)acetonitrile;

(E)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b7pyridin-2-yl) methyl)-W'-hydroxybenzimidamide;

(Z)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b7pyridin-2-yl) methyl )-N- hydroxybenzimidamide;

2-((1r,4r)-4-(2-(2-(3-Hydroxyazetidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-phenylacetamide ;

2- (( 1r,4r)-4- ( 2- (( 1H -pyrazol-5-yl)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)- yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-cyclohexylacetamide ; 2- (( 1r,4r)-4- ( 2- ( 4-Chloro-1H -pyrazol-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H) -yl)cyclohexyl)acetonitrile;

N-((3R,5R)-Adamantan-1-yl)-2-(1-((1r,4r)-4-(cyanomethyl)c¡clohex¡l)-1,6-dihydroimidazo[4, 5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1r,4r)-4-hydroxycyclohexyl)acetamide;

N-(4-cyanobenzyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)acetamide;

1 -((1 -((1r,4r)-4-(C¡anomethyl)cyclohex¡l)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)urea;

2-(('1r,4r)-4-(2-(Thiazol-4-ylmethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile ;

2-((1S,4r)-4-(2-(2-((S)-3-Hydroxypyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-(pyridin-4-yloxy)ethyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-neopentylacetamide ; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-fluorobenzyl)acetamide;

Phenyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ; N-benzyl-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) acetamide;

2-((1r,4r)-4-(2-(2-Oxo-2-(pyrrolidin-1-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(3-Hydroxy-3-phenylpyrrolidin-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1l(6H)- yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(2-Aminopyrimidin-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile; 2-((1r,4r)-4-(2-(2-Aminopyrimidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile;

4-(2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamido )bicyclo[2,2,1]heptane-1-carboxamide;

2- (( 1r,4r)-4- ( 2- ( 1H -imidazol-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2,2,2-trifluoroethyl)acetamide;

4-(2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamido )bicyclo[2,2,2]octane-1-carboxamide;

2- (( 1r,4r)-4- ( 2- ( 1H -pyrazol-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

(EZ)-N-((1-((lr,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxyisobutyrimidamide;

2-((1r,4r)-4-(2-(2H-Tetrazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4,4-dimethylcyclohexyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1-methylpiperidin-4-yl)acetamide;

2- (( 1r,4r)-4- ( 2- ( 2- ( 1 ,1-Dioxidothiomorpholino)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H )-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( cyclohexylmethyl)acetamide;

1 -((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-phenylurea;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-methoxy-2-methylpropyl)acetamide;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)-3-methoxypropanimidamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 3,5-dimethylcyclohexyl)acetamide;

4-(4-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)piperidine -1 -yl)benzonitrile;

N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzenesulfonamide ;

N-((1S,4R)-Bicyclo[2,2,1]heptan-2-yl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[ 4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(difluoromethoxy)benzyl)acetamide;

1- ((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-((3-hydroxyoxetan-3-yl)methyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridine-2-carboxamide;

2-((1r,4r)-4-(2-(3-Methyl-1H-pyrazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H) -yl)cyclohexyl)acetonitrile;

4-cyano-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)benzamide;

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( tetrahydro-2H-thiopyran-4-yl)acetamide;

1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-N-(1-methylpiperidin-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-carboxamide;

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)acetimidamide ; 2-((1r,4r)-4-(2-(2-(4-Benzylpiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(4-Hydroxy-4-(pyridin-2-yl)piperidine-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b] pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(2-(Methylamino)pyrimidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile; 2-(( 1r,4r)-4-(2-(2-Oxo-2-(piperidin-1 -yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(4'-(Methylsulfonyl)-[1,1'-biphenyl]-4-yl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile; 2-((1 r,4r)-4-(2-(4-Benzoylphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 2-cyclopropylacetamide;

(EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-2-cyclohexyl-N'-hydroxyacetimidamide;

4-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)benzonitrile;

4-cyano-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)benzenesulfonamide;

2-((1r,4r)-4-(2-(2-(Methylthio)pyrimidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (trimethylsilyl)methyl)acetamide;

2-(( 1r,4r)-4-(2-(4-(T-rimethylsilyl)cyclohexyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile;

(EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxy-3,3-dimethylbutanimidamide;

2-(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-hydroxy-2-phenylethyl)acetamide;

(EZ)-N-((1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxy-2-phenylacetimidamide;

1 -(2-(1 -((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetyl )piperidine-4-carbonitrile;

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2,3 -dihydroxypropyl)acetamide;

2-((7r,4rj-4-(2-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine- 1(6H)-yl)cyclohexyl)acetonitrile;

4-(2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamidiethyl do)benzylphosphonate;

(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methylphenylcarbamate;

(EZ)-N-((1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) -N'-hydroxycyclopropanecarboximidamide;

2-(1-((7r,4rj-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(pyridin -3-yl)acetamide;(z)-N'-((1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)methoxy)-2-cyclopropylacetimidamide;

2-((7r,4r)-4-(2-(Methoxymethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

1 -((7r,4f^-4-(cyanomethyl)cyclohexyl)-N-(2-hydroxyethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide 5-(1-((7r,4f^-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)picolinonitrile;

1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-N-(2-hydroxy-2-methylpropyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-carboxamide;

2-(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( pyridin-4-yl)acetamide; 2-((7r,4rj-4-(2-(Thiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(4-(4-(Hydroxymethyl)benzoyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile; 1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-N-(oxetan-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2 -carboxamide; 2- (( 1r,4r)-4- ( 2- ( 1H -pyrazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)benzimidamide;

(EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxy-3-methoxypropanimidamide;

2-((1r,4r)-4-(2-(((4-(4-Ethynylbenzoyl)benzyl)oxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(2-((R)-3-Hydroxypyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

3- (1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)azetidine-1- ethyl carboxylate;

2-((1r,4r)-4-(2-((3-isopropyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)imidazo[4,5-d]pyrrolo [2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-((4-(4-Ethynylbenzoyl)phenoxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(hydroxymethyl)bicyclo[2,2,1]heptan-1-yl)acetamide;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide;

2- (1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1S,4S)-4-(trimethylsilyl)cyclohexyl)acetamide;

1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-((1-hydroxycycloheptyl)methyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine- 2-carboxamide;

Isobutyl ((1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ;

N-(2-cyanoethyl)-1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide ; N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)cyclohexanecarboxamide ;

2-((1r,4r)-4-(2-(3-Cyclopropyl-4,5-dihydro-1,2,4-oxadiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)cyclohexanesulfonamide ;

2-((7r,4r)-4-(2-(((Dimethyl(oxo)-A6-sulfanilidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(4-(Pentafluoro-A6-sulfanyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile; N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 1 H-pyrazole-4-carboxamide;

1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-N-(2-methoxyethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide ; (1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl(cyclohexylmethyl)carbamate;

2-((1r,4r)-4-(2-(1-acetylazetidin-3-yl)imizo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile; N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzamide ;

2-((1r,4r)-4-(2-(2-((R)-2-(Hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)isobutyrimidamide;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)cyclopropanecarboximidamide;

(3R,5R,7R,E*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)methoxy)adamantane-1-carboximidamide;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)-2-(piperidin-1-yl)acetimidamide;

Neopentyl ((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ;

1- ((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-(cyclohexylmethyl)urea;

(3R,5R,7R)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)methyl)adamantane-1-carboximidamide;

tert-Butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) carbamate; 2-((7rJ4f^-4-(2-(Azetidin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

(2-methoxy(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyltil) carbamate; 2-((1r,4r)-4-(2-((((R)-methyl(oxo)(phenyl)-A6-sulfanylidene)amino)methyl)imidazo[4,Sd]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-((((S)-methyl(oxo)(phenyl)-A6-sulfanylidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(1-acetylpiperidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile;

2-((lr,4r)-4-(2-((3-cyclopropyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)imidazo[4,5-d]pyrrolo [2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(( 1r,4r)-4- ( 2- ( 1 -(Oxazol-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b] pyridine-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( ( 1r,4r)-4- (trimethylsilyl)cyclohexyl)acetamide;

2-((1r,4r)-4-(2-(4-(4-Ethynylbenzoyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

2-((lr,4r)-4-(2-(4-(4-Ethynylbenzoyl)phenethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

1-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-isopropylurea; 1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-isopropyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide; 1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(3-methoxypropyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide ;

2- (1 -((1r,4r)-4-cyanocyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(4-( methylsulfonyl)phenyl)acetamide;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-cyclopropyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide; 2-((1r,4r)-4-(2-(4-methoxypiperidine-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile; 1 -(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carbonyl)piperidine-4- carbonitrile;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(tetrahydro-2H-pyran-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b ]pyridine-2-carboxamide;

1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(1-methoxypropan-2-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-carboxamide;

2-((1r,4r)-4-(2-(morpholine-4-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(4-hydroxypiperidine-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile; 2-(4-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)- ethyl 1H-pyrazol-1-yl)acetate;

2-((1r,4r)-4-(2-(2,4-dimethyloxazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(2,4-dimethylthiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile;

2-(4-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)- 1H-pyrazol-1-yl)-N-cyclopropylacetamide;

2-((1rJ4r)-4-(2-(2-aminopyridin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(( 1r,4r)-4- ( 2- ( 1 -(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)imidazo[4,5-d]pyrrolo[2,3- b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-8-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-7-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide;

2-((1r,4r)-4-(2-(2,5,8,11-Tetraoxatridecan-13-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H )-yl)cyclohexyl)acetonitrile; N-(2-(2-(2-Aminoethoxy)ethoxy)ethyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d] pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-((1r,4r)-4-(2-((2-(2-methoxyethoxy)ethoxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile; 2-((1S,4r)-4-(2-(2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

(1-((1r,4A)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl(3S,5S, 7S)-adamantan-1-ylcarbamate;

2-((1r,4r)-4-(2-(2-(4-Methoxypiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

N-((3R,5R,7R)-Adamantan-1-ylmethyl)-2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d] pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-((1 r,4r)-4-(2-(tert-butoxymethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile.;

2- ( ' ( 1r,4r)-4-' ( 2- (( 5-Oxo-3-phenyl-1 ,2,4-oxadiazol-4(5H)-yl)methyl)imidazo[4,5-d ]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

(N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) -N'-hydroxycyclohexanecarboximidamide;

2-(4-(2-(2-Oxo-2-(piperidin-1-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo [2,2,2]octan-1-yl)acetonitrile, 2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5 -d]pyrrolo[2,3-b]pyridin-2-yl)acetamide,

2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)-N-phenylacetamide; 2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)-N-(cyclohexylmethyl)acetamide and

2-(1-(4-(Cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)-N-methylacetamide

[0074] Another aspect of the description is a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-hydroxy-2-methylpropyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( cyclopropylmethyl)acetamide;

N-(2-cyanoethyl)-2-(1-((1 R,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)acetamide;

2-(1-(('1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (tetrahydro-2Hpyran-4-yl)acetamide;

2-((1r,4r)-4-(2-(2-Oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(hydroxymethyl)phenyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(cyanomethyl)phenyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (tetrahydro-2Hpyran-4-yl)methyl)acetamide;

2-((1r,4r)-4-(2-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(2-(3-Hydroxyazetidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-phenylacetamide ;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-cyclohexylacetamide ; N-((3R,5R)-Adamantan-1-yl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[ 2,3-b]pyridin-2-yl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1r,4r)-4-hydroxycyclohexyl)acetamide;

N-(4-cyanobenzyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)acetamide;

1 -((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)urea ;

2-((1 S,4r)-4-(2-(2-((S)-3-Hydroxypyrrolidin-1 -yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3- b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-(pyridin-4-yloxy)ethyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-neopentylacetamide ; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-fluorobenzyl)acetamide;

N-benzyl-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) acetamide; 2-(( 1r,4r)-4-(2-(2-Oxo-2-(pyrrolidin-1 -yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(3-Hydroxy-3-phenylpyrrolidin-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile;

4-(2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamido )bicyclo[2,2,1]heptane-1-carboxamide;

2-(1-((7r,4r>4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2 ,2,2-trifluoroethyl)acetamide;

4-(2-(1-((7r,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamido) bicyclo[2,2,2]octane-1-carboxamide;

2-(1-((7r,4r,)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (4,4-dimethylcyclohexyl)acetamide;

2-(1 -((7r,4r,)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (1-methylpiperidin-4-yl)acetamide;

2-((7r,4r,)-4-(2-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2-(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( cyclohexylmethyl)acetamide;

2-(1-((7r,4r,1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (2-methoxy-2-methylpropyl)acetamide;

2-(1-(( 7r,4r^-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 3,5-dimethylcyclohexyl)acetamide;

N-((1S,4R)-Bicyclo[2,2,1]heptan-2-yl)-2-(1-((7r,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo [4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((7r,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (4-(difluoromethoxy)benzyl)acetamide;

1-((7r,4r,)-4-(Cyanomethyl)cyclohexyl)-N-((3-hydroxyoxetan-3-yl)methyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridine-2-carboxamide;

4-cyano-N-((1-((7r,4r1-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) methyl)benzamide;

2-(1-((7r,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(tetrahydro -2H-thiopyran-4-yl)acetamide;

1 -((7r,4r,)-4-(cyanomethyl)cyclohexyl)-N-(1-methylpiperidin-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b] pyridine-2-carboxamide;

2-((7r,4r}-4-(2-(2-(4-Benzylpiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

2-((7r,4r}-4-(2-(4-Hydroxy-4-(pyridin-2-yl)piperidine-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b] pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((7r,4r}-4-(2-(2-Oxo-2-(piperidin-1-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

N-((1-((7r,4r,)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) -2-cyclopropylacetamide;

2-(1-((7r,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( trimethylsilyl)methyl)acetamide;

2-(1-((7r,4rM-(C¡anomethyl)cyclohex¡l)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (2-hydroxy-2-phenylethyl)acetamide;

1-(2-(1-((7r,4r,)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) acetyl)piperidine-4-carbonitrile;

2-(1-((7r,4rj-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2 ,3-dihydroxypropyl)acetamide;

2-((7r,49-4-(2-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine- 1(6H)-yl)cyclohexyl)acetonitrile;

4-(2-(1-((7r,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) diethyl acetamido)benzylphosphonate;

2-(1-((7r,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(pyridin -3-yl)acetamide;1-((7r,4r1-4-(cyanomethyl)cyclohexyl)-N-(2-hydroxyethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b ]pyridine-2-carboxamide;1-((7r,4r1-4-(cyanomethyl)cyclohexyl)-N-(2-hydroxy-2-methylpropyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2 ,3-b]pyridine-2-carboxamide;

2-(1-((7r,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(pyridin -4-yl)acetamide;1-((7r,4rj-4-(cyanomethyl)cyclohexyl)-N-(oxetan-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridine-2-carboxamide;2-((7r,4r1-4-(2-(2-((R)-3-Hydroxypyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-d ]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(hydroxymethyl)bicyclo[2,2,1]heptan-1-yl)acetamide;

1-((7r,4r1-4-(Cyanomethyl)cyclohexyl)-N-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide;

2-(1-((7r,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 1S,4S)-4-(trimethylsilyl)cyclohexyl)acetamide;

1-((7r,4r1-4-(Cyanomethyl)cyclohexyl)-N-((1-hydroxycycloheptyl)methyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2 -carboxamide;

N-(2-cyanoethyl)-1-((7r,4r1-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide; 1-((7r,4r1-4-(cyanomethyl)cyclohexyl)-N-(2-methoxyethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide; 2- (( 7r;4r>-4-(2-(2-((R)-2-(Hydroxymethyl)pyrrolidin-1 -yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( ( 1r,4r)-4- (trimethylsilyl)cyclohexyl)acetamide;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-isopropyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide; 1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(3-methoxypropyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide ;

2- (1 -((1r,4r)-4-cyanocyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(4-( methylsulfonyl)phenyl)acetamide;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-cyclopropyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide; 2-((1r,4r)-4-(2-(4-methoxypiperidine-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile; 1 -(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,Sd]pyrrolo[2,3-b]pyridine-2-carbonyl)piperidine-4-carbonitrile;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(tetrahydro-2H-pyran-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b ]pyridine-2-carboxamide;

1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(1-methoxypropan-2-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-carboxamide;

2-((1r,4r)-4-(2-(morpholine-4-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(4-hydroxypiperidine-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile; 2-((1r,4r)-4-(2-(2-((S)-2-(Hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(2-(4-methoxypiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

N-((3R,5R,7R)-Adamantan-1-ylmethyl)-2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d] pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide; and

2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)-N-methylacetamide.

[0075] Another aspect of the disclosure is a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

Phenyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ; (EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxyisobutyrimidamide;

1 -((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-phenylurea;

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)acetimidamide ; (EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-2-cyclohexyl-N'-hydroxyacetimidamide;

(EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxy-3,3-dimethylbutanimidamide;

(E ^z )-N-((1-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methyl)-N'-hydroxy-2-phenylacetimidamide;

(EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxycyclopropanecarboximidamide;

(EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxy-3-methoxypropanimidamide;

Isobutyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ;

N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)cyclohexanecarboxamide ;

N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 1 H-pyrazole-4-carboxamide;

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzamide ;

Neopentyl ((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ;

1 -((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-(cyclohexylmethyl)urea;

(3R,5R,7R)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)methyl)adamantane-1-carboximidamide;

tert-butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ;

1 -((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-isopropylurea; (N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) -N'-hydroxycyclohexanecarboximidamide;

2-((1r,4r)-4-(2-(((Dimethyl(oxo)-A6-sulfanylidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile,

2-((1r,4r)-4-(2-((((R)-Methyl(oxo)(phenyl)-A6-sulfanilidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile,

2-((7r,4r,M-(2-((((S)-methyl(oxo)(phenyl)-A6-sulfanylidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3- b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

(Z*)-N'-((1-((7r,4rM-(C¡anomethyl)cyclohex¡l)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)methoxy)-3-methoxypropanimidamide,

(Z)-N'-((1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methoxy)-2-cyclopropylacetimidamide,

(Z*)-N'-((1-((ir,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)methoxy)benzimidamide,

(Z*)-N'-((1-((ir,4r1-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)methoxy)isobutyrimidamide;

(Z*)-N'-((1-((ir,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)methoxy)cyclopropanecarboximidamide;

(3R,5R,7R,E*)-N'-((1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridine-2-yl)methoxy)adamantane-1-carboximidamide;

(Z*)-N'-((1-((ir,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)methoxy)-2-(piperidin-1-yl)acetimidamide;

N-((1 -((ir,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzenesulfonamide;

4-cyano-N-((1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) methyl)benzenesulfonamide, and

N-((1 -((ir,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)cyclohexanesulfonamide.

[0076] Another aspect of the disclosure is a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

((1 -((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate phenyl; (EZ)-N-((1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) -N'-hydroxyisobutyrimidamide;

1 -((1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)-3 -phenylurea;

N-((1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)acetimidamide; (EZ)-N-((1-((ir,4r1-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) methyl)-2-cyclohexyl-N'-hydroxyacetimidamide;

(EZ)-N-((1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) -N'-hydroxy-3,3-dimethylbutanimidamide;

(Ez)-N-((1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) -N'-hydroxy-2-phenylacetimidamide;

(EZ)-N-((1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) -N'-hydroxycyclopropanecarboximidamide;

(EZ)-N-((1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) -N'-hydroxy-3-methoxypropanimidamide;

Isobutyl ((1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ;

N-((1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)cyclohexanecarboxamide;

N-((1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)-1 H-pyrazole-4-carboxamide;

N-((1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzamide;

neopentyl ((1 -((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dlhydrolmidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate;

1 -((1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)-3 -(cyclohexylmethyl)urea;

(3R,5R,7R)-N-((1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine- 2-yl)methyl)adamantane-1-carboximidamide;

tert-Butyl ((1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate; 1 -((1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)-3- isopropylurea, and (N-((1-((ir,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) methyl)-N'-hydroxycyclohexanecarboximidamide

[0077] Another aspect of the disclosure is a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

2- ((ir,4r1-4-(2-(((Dimethyl(oxo)-A6-sulfanylidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H )-yl)cyclohexyl)acetonitrile;

2-((ir,4A)-4-(2-((((R)-Methyl(oxo)(phenyl)-A6-sulfanilidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile and

2-((1r,4r)-4-(2-((((S)-methyl(oxo)(phenyl)-A6-sulfanylidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0078] A further aspect of the disclosure is a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2 -yl)methoxy)-3-methoxypropanim idamide;

(Z)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)methoxy)-2-cyclopropylacetimidamide;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)benzimidamide;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)isobutyrimidamide;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)cyclopropanecarboximidamide;

(3R,5R,7R,E*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)methoxy)adamantane-1-carboximidamide; and

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)-2-(piperidin-1-yl)acetimidamide.

[0079] Another aspect of the disclosure is a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzenesulfonamide ;

4-cyano-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)benzenesulfonamide; and

N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)cyclohexanesulfonamide .

[0080] Another aspect of the disclosure is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-hydroxy-2-methylpropyl)acetamide;

2- (( 1r,4r)-4- ( 2- ( 1H -imidazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( cyclopropylmethyl)acetamide;

N-(2-cyanoethyl)-2-(1-((1 R,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( tetrahydro-2H-pyran-4-yl)acetamide;

2-((1r,4r)-4-(2-(2-Oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(hydroxymethyl)phenyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(cyanomethyl)phenyl)acetamide;

2- (( 1r,4r)-4- ( 2- ( 1 H-1 ,2,4-T riazol-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (tetrahydro-2Hpyran-4-yl)methyl)acetamide;

2-((1r,4A)-4-(2-(Oxazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1/-,4r)-4-(2-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1(6H)-yl)cyclohexyl)acetonitrile;

2- (( 1r,4r)-4- ( 2- ( 2H-1 ,2,3-T riazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

(E)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-bjpyridin-2-yl) methyl) -N'- hydroxybenzimidamide;

(Z)-N-('(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a^pyrrolo[2,3-bJpyridin-2-yl) methyl) -N'-hydroxybenzimidamide;

2-((1r,4r)-4-(2-(2-(3-Hydroxyazetidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-phenylacetamide ;

2- (( 1r,4r)-4- ( 2- (( 1H -pyrazol-5-yl)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)- yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-cyclohexylacetamide ; 2- (( 1r,4r)-4- ( 2- ( 4-Chloro-1H -pyrazol-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H) -yl)cyclohexyl)acetonitrile; N-((3F,5R)-Adamantan-1 -yl)-2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[ 2,3-b]pyridin-2-yl)acetamide;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1r,4r)-4-hydroxycyclohexyl)acetamide;

N-(4-cyanobenzyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)acetamide;

1 -((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)urea ;

2-((1r,4r)-4-(2-(Thiazol-4-ylmethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1 S,4r)-4-(2-(2-((S)-3-Hydroxypyrrolidin-1 -yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3- b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-(pyridin-4-yloxy)ethyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-neopentylacetamide ; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-fluorobenzyl)acetamide;

Phenyl ((1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ; N-benzyl-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) acetamide; 2-(( 1r,4r^-4-(2-(2-Oxo-2-(pyrrolidin-1 -yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(3-Hydroxy-3-phenylpyrrolidin-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)- yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(2-Aminopyrimidin-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) ytryl acetone;

2-((1r,4r)-4-(2-(2-Aminopyrimidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile;

4-(2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamido )bicyclo[2,2,1]heptane-1-carboxamide;

2- (( 1r,4r)-4- ( 2- ( 1H -imidazol-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2,2,2-trifluoroethyl)acetamide;

4-(2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamido )bicyclo[2,2,2]octane-1-carboxamide;

2- (( 1r,4r)-4- ( 2- ( 1H -pyrazol-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

(EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxyisobutyrimidamide;

2-((1r,4r)-4-(2-(2H-Tetrazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile;

2-(1-(( 1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4,4-dimethylcyclohexyl)acetamide;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1-methylpiperidin-4-yl)acetamide;

2-((1r,4r)-4-(2-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H )-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( cyclohexylmethyl)acetamide;

1- ((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-phenylurea;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-methoxy-2-methylpropyl)acetamide;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)-3-methoxypropanimidamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 3,5-dimethylcyclohexyl)acetamide;

4-(4-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)piperidine -1 -yl)benzonitrile;

N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzenesulfonamide ;

N-((1S,4R)-Bicyclo[2,2,1]heptan-2-yl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[ 4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(difluoromethoxy)benzyl)acetamide;

1- ((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-((3-hydroxyoxetan-3-yl)methyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridine-2-carboxamide;

2-((1r,4r)-4-(2-(3-Methyl-1H-pyrazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H) -yl)cyclohexyl)acetonitrile;

4-cyano-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)benzamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( tetrahydro-2H-thiopyran-4-yl)acetamide;

1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-N-(1-methylpiperidin-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-carboxamide;

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)acetimidamide ; 2-((1r,4rJ-4-(2-(2-(4-Benzylpiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1( 6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4rJ-4-(2-(4-Hydroxy-4-(pyridin-2-yl)piperidine-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(2-(Methylamino)pyrimidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile; 2-((1r,4r)-4-(2-(2-oxo-2-(piperidin-1-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(4'-(Methylsulfonyl)-[1,1'-biphenyl]-4-yl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile; 2-((1r,4r)-4-(2-(4-Benzoylphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 2-cyclopropylacetamide;

(EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-2-cyclohexyl-N'-hydroxyacetimidamide;

4-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)benzonitrile;

4-cyano-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)benzenesulfonamide;

2-((1r,4r)-4-(2-(2-(Methylthio)pyrimidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl-N-(( trimethylsilyl)methyl)acetamide,

2-((1r,4r)-4-(2-(4-(Trimethylsilyl)cyclohexyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile ;

(EZ)-N-((1-((1r,4rj-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) methyl)-N'-hydroxy-3,3-dimethylbutanimidamide;

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-hydroxy-2-phenylethyl)acetamide,

(EZ)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxy-2-phenylacetimidamide;

1-(2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetyl )piperidine-4-carbonitrile;

2-(1-((1r,4rj-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2 ,3-dihydroxypropyl)acetamide;

2-(( ír,4r)-4-(2-(2-(4,4-Difluoropiperidin-1 )-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b] pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

4-(2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamidiethyl do)benzylphosphonate;

(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl phenylcarbamate;

(EZ)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxycyclopropanecarboximidamide;

2-(1-((1r,4rj-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(pyridin -3-yl)acetamide;(z)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)methoxy)-2-cyclopropylacetimidamide;

2-((1r,4r)-4-(2-(Methoxymethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(2-hydroxyethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide ; 5-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)picolinonitrile;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(2-hydroxy-2-methylpropyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-carboxamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( pyridin-4-yl)acetamide; 2-(( ír,4r)-4-(2-(Thiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(4-(4-(Hydroxymethyl)benzoyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile; 1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(oxetan-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2 -carboxamide; 2- (( 1r,4r)-4- ( 2- ( 1H -pyrazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)benzimidamide;

(Ez)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxy-3-methoxypropanimidamide;

2-((1r,4r)-4-(2-(((4-(4-ethynylbenzoyl)benzyl)oxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2- (( 1r,4r)-4-(2-(2-((R)-3-Hydroxypyrrolidin-1 -yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

3- (1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)azetidine-1- ethyl carboxylate;

2-((1r,4r)-4-(2-((3-Isopropyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)imidazo[4,5-d]pyrrolo [2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-((4-(4-Ethynylbenzoyl)phenoxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(hydroxymethyl)bicyclo[2,2,1]heptan-1-yl)acetamide;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide;

2- (1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-((1S ,4S)-4(trimethylsilyl)cyclohexyl)acetamide;

1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-((1-hydroxycycloheptyl)methyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine- 2-carboxamide;

Isobutyl ((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ;

N-(2-cyanoethyl)-1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide ; N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)cyclohexanecarboxamide ;

2-((1r,4r)-4-(2-(3-Cyclopropyl-4,5-dihydro-1,2,4-oxadiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)cyclohexanesulfonamide ;

2-((1r,4r)-4-(2-(((Dimethyl(oxo)-A6-sulfamlidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(4-(Pentafluoro-A6-sulfaml)feml)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile; N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 1 H-pyrazole-4-carboxamide;

1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-N-(2-methoxyethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide ; (1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl(cyclohexylmethyl)carbamate;

2-((1r,4r)-4-(2-(1-acetylazetidin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile;

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzamide ;

2-((1r,4r)-4-(2-(2-((R)-2-(Hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)isobutyrimidamide;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)cyclopropanecarboximidamide;

(3R,5R,7R,E*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)methoxy)adamantane-1-carboximidamide;

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)-2-(piperidin-1-yl)acetimidamide;

Neopentyl ((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate ;

1- ((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-(cyclohexylmethyl)urea;

(3R,5R,7R)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)methyl)adamantane-1-carboximidamide;

tert-Butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) carbamate; 2-((1r,4r)-4-(2-(Azetidin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-(2-methoxy)-yl) methylethyl)carbamate;

2-((1r,4r)-4-(2-((((R)-methyl(oxo)(phenyl)-A6-sulfanylidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-((((S)-methyl(oxo)(feml)-A6-sulfamlidene)ammo)methyl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridm-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1r,4r)-4-(2-(1-Acetylpiperidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridm-1(6H)-yl)cyclohexyl) acetonitrile;

2-((lr,4r)-4-(2-((3-cyclopropyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)imidazo[4,5-d]pyrrolo [2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(( 1r,4r)-4- ( 2- ( 1 -(Oxazol-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b] pyridine-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1 r,4r)-4-(trimethylsilyl)cyclohexyl)acetamide;

2-((1r,4r)-4-(2-(4-(4-Ethynylbenzoyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

2-((lr,4r)-4-(2-(4-(4-Ethynylbenzoyl)phenethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile;

1-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-isopropylurea; 1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-isopropyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide; 1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(3-methoxypropyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide ;

2- (1 -((1r,4r)-4-cyanocyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(4-( methylsulfonyl)phenyl)acetamide;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-cyclopropyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide; 2-((1r,4r)-4-(2-(4-methoxypiperidine-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile; eleven -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carbonyl)piperidine-4-carbonitrile;

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(tetrahydro-2H-pyran-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b ]pyridine-2-carboxamide;

1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(1-methoxypropan-2-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-carboxamide;

2-((1r,4r)-4-(2-(morpholine-4-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-((1 r,4r)-4-(2-(4-hydroxypiperidine-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile; 2-(4-(1 -((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -1H-pyrazol-1-yl)ethyl acetate;

2- (( 7r, 4r)-4-(2-(2,4-dimethyloxazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile;

2-((lr,4r)-4-(2-(2,4-dimethylthiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile;

2-(4-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)- 1H-pyrazol-1-yl)-N-cyclopropylacetamide;

2-((1r,4r)-4-(2-(2-aminopyridin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile;

2-(( 1r,4r)-4- ( 2- ( 1 -(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)imidazo[4,5-d]pyrrolo[2,3- b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-8-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-7-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide;

2-((1r,4r)-4-(2-(2,5,8,11-Tetraoxatridecan-13-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H )-yl)cyclohexyl)acetonitrile; N-(2-(2-(2-Aminoethoxy)ethoxy)ethyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d] pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-((1r,4r)-4-(2-((2-(2-methoxyethoxy)ethoxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile; 2-((1S,4r)-4-(2-(2-((S)-2-(hydroxymethyl)pyrrolidin-1 -yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl (3S,5S, 7S)-adamantan-1-ylcarbamate;

2-((1r,4r)-4-(2-(2-(4-methoxypiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile;

N-((3R,5R,7R)-Adamantan-1 -ylmethyl)-2-(1 -((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d ]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide;

2-((1r,4r)-4-(2-(tert-butoxymethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

2- ( ' ( 1r,4r)-4-' ( 2- (( 5-Oxo-3-phenyl-1 ,2,4-oxadiazol-4(5H)-yl)methyl)imidazo[4,5-d ]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;

(N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl) -N'-hydroxycyclohexanecarboximidamide;

2-(4-(2-(2-Oxo-2-(piperidin-1-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo [2,2,2]octan-1-yl)acetonitrile, 2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5 -d]pyrrolo[2,3-b]pyridin-2-yl)acetamide, 2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo [4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-phenylacetamide; 2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)-N-(cyclohexylmethyl)acetamide and

2-(1-(4-(Cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)-N-methylacetamide

[0081] A "pharmaceutically acceptable salt" is a salt of a compound that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See generally S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 66, 1-19 (1977) and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. The compounds of the invention may possess a group sufficiently acidic, a sufficiently basic group, or both types of functional groups, and consequently react with various inorganic or organic bases and inorganic and organic acids to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates , propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates , phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, and -hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0082] If the compound of the invention contains at least one basic nitrogen, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, and phosphoric acid, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid , succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha- hydroxy, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an acid aromatic, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those exemplified herein document, and any other acids and mixtures thereof that are considered acceptable equivalents or substitutes in light of ordinary level of skill in this technology.

[0083] Not all embodiments of pharmaceutically acceptable salts of compounds according to this invention may be equally suitable for development, since compounds that are sufficiently weakly basic ( eg, pKa about 4) may not form salts stable enough for development purposes. See, for example, GA Stephenson et al., J. Pharm. Sciences 100(5), 1607-17 (2011) "Physical stability of salts of weak bases in the solid state". Some embodiments of this invention are envisioned to encompass cocrystallized forms of a compound according to this invention with a suitable cocrystal former. The design and properties of co-crystals for pharmaceutical use and methods for making and characterizing them have been provided, for example, in N. Shan, et al., Drug Discovery Today, 13 (9/10), 440-46 (2008 ). "The role of cocrystals in pharmaceutical science"; N. Qiao, et al., Intl. J. Pharmaceutics, 419, 1-11 (2011) "Pharmaceutical cocrystals: An overview"; R. Thakuria, et al., Intl. J. Pharmaceutics, 453, 101-25 (2013) "Pharmaceutical cocrystals and poorly soluble drugs".

[0084] The compounds of the invention, including their pharmaceutically acceptable salts, alone or in combination (collectively, "active agent" or "active agents") of the present invention are useful as JAK inhibitors in the methods of the disclosure. Said methods for modulating JAK activity comprise exposing JAK to an effective amount of at least one chemical compound of the invention. Embodiments of this invention inhibit JAK activity.

[0085] In some embodiments, the JAK inhibitor is used in a subject diagnosed with or suffering from a disease, disorder, or medical condition mediated by JAK activity, such as those described herein. Symptoms or disease states are intended to be included within the scope of "disease, disorders, or medical conditions."

[0086] Accordingly, the disclosure is directed to methods of using the active agents described herein to treat subjects diagnosed with or suffering from a JAK-mediated disease, disorder, or medical condition. The term "treat" or "treated", as used herein, refers to the administration of an active agent or composition of the disclosure to a subject for the purpose of affecting a therapeutic or prophylactic benefit through JAK modulation. Treatment includes reversing, ameliorating, alleviating, inhibiting the progression of, lessening the severity, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder, or condition mediated by modulation of JAK activity. The term "subject" refers to a mammalian patient in need of such treatment, such as a human. The term "inhibitors" or "inhibitor" refers to compounds that decrease, prevent, inactivate, desensitize, or downregulate JAK expression or activity.

[0087] Aspects of this disclosure provide JAK inhibitors for the prevention and/or control of an excessive inflammatory response. Embodiments of JAK inhibitors according to this invention are pan-JAK inhibitors.

[0088] Unless otherwise indicated, the term "JAK inhibitor physicochemical properties" refers to the corresponding named properties as follows:

as given in the description of the compounds Ex. 1-5, 10, 22, 34, 38, 55, 74 and 85, in the case of molar masses; as determined in accordance with the respective definitions, in the case of numbers of H-link donors, acceptors, and spin-links; and

measured with reference to Table 1a, column 2, in the case of plasma concentrations, and Table 7, columns 3 and 4, in the case of the A-B permeability coefficients in the presence of the P-gp inhibitor and the coefficients of permeability B-A.

[0089] Aspects of this disclosure provide methods of inhibiting JAK, comprising exposing a JAK receptor to a JAK inhibitor that is characterized as having the following JAK inhibitor physicochemical properties: a plasma concentration in the range of about 0.1 ng/mL to about 60 ng/mL, cLog P in the range of about 0.1 to about 2.8, A-B permeability coefficients in the presence of a P-gp inhibitor in the range of about 0.1 to about 2.5, B-A permeability coefficients in the range of about 0.5 to about 20, tPSA in the range of about 85 to about 120.

[0090] In other aspects of JAK inhibition methods according to this disclosure, the plasma concentration is in the range of about 10 ng/ml to about 20 ng/ml.

[0091] In other aspects of JAK inhibition methods in accordance with this disclosure, cLogP is in the range of about 0.8 to about 1.4.

[0092] In other aspects of methods for inhibiting JAK in accordance with this disclosure, the AB permeability coefficient in the presence of a P-gp inhibitor is in the range of about 0.6 to about 1.5.

[0093] In other aspects of the JAK inhibition methods according to this disclosure, the B-A permeability coefficient is in the range of about 0.5 to about 5.

[0094] In other aspects of the JAK inhibition methods according to this disclosure, tPSA is in the range of about 100 to about 120.

[0095] Other aspects of this disclosure provide methods for inhibiting JAK, comprising exposing a JAK receptor to a JAK inhibitor that is further characterized as having the following JAK inhibitor physicochemical properties: mass in the range of about 300 gmol- 1 to about 500 g mol-1, a number of hydrogen bond donors in the range of about 2 to about 3, a number of hydrogen bond acceptors in the range of about 4 to about 5, and a number of twist links in the range of about 3 to about 6, in addition to the plasma concentrations, clogP values, permeability coefficients, and tPSA values described above for JAK inhibition methodologies in accordance with this disclosure.

[0096] In other aspects of JAK inhibition methods according to this disclosure, the molar mass is in the range of about 340 g mol-1 to about 430 g mol-1.

[0097] In other aspects of methods for inhibiting JAK in accordance with this disclosure, the number of spindles is in the range of about 5 to about 6.

[0098] Aspects of this disclosure provide methods of treating inflammation in the gastrointestinal tract of a subject, comprising administering to a subject a pharmaceutically effective amount of a JAK inhibitor that is characterized as having the following JAK inhibitor physicochemical properties : A plasma concentration in the range of about 0.1 ng/mL to about 60 ng/mL, A-B permeability coefficients in the range of 0.1 to 2.5, A-B permeability coefficients in the range of 0.5 to 20, A-B permeability coefficients in the range of 0.5 to 20, tPSA in the range of about 85 to about 120.

[0099] In other aspects of methods for treating inflammation in the gastrointestinal tract in accordance with this disclosure, the plasma concentration is in the range of about 10 ng/ml to about 20 ng/ml.

[0100] In other aspects of methods for treating inflammation in the gastrointestinal tract in accordance with this disclosure, cLogP is in the range of about 0.8 to about 1.4.

[0101] In other aspects of methods for treating inflammation in the gastrointestinal tract in accordance with this disclosure, the A-B permeability coefficient is in the presence of a P-gp inhibitor in the range of about 0.6 to about 1, 5.

[0102] In other aspects of the methods for treating inflammation in the gastrointestinal tract according to this disclosure, the coefficient of permeability B-A is in the range of about 0.5 to about 5.

[0103] In other aspects of methods for treating inflammation in the gastrointestinal tract in accordance with this disclosure, tPSA is in the range of about 100 to about 120.

[0104] Other aspects of this disclosure provide methods of treating inflammation in the gastrointestinal tract of a subject in which the physicochemical properties of the JAK inhibitor are further characterized. by having the following JAK inhibitor physicochemical properties: a molar mass in the range of about 300 g mol-1 to about 500 g mol-1, a number of hydrogen bond donors in the range of about 2 to about 3, a number of hydrogen bond acceptors in the range of about 4 to about 5, and a number of spin bonds in the range of about 3 to about 6, in addition to plasma concentrations, values of cLogP, permeability coefficients and tPSA values described above for methodologies of treating inflammation in accordance with this disclosure.

[0105] In other aspects of methods for treating inflammation in the gastrointestinal tract in accordance with this disclosure, the molar mass is in the range of about 350 g mol-1 to about 430 g mol-1.

[0106] In other aspects of methods for treating inflammation in the gastrointestinal tract in accordance with this disclosure, the number of twist links is in the range of about 5 to about 6.

[0107] Embodiments of JAK inhibitors according to this invention have the following JAK physicochemical properties: a plasma concentration in the range of about 0.1 ng/ml to about 60 ng/ml, a cLogP in the range of 0.1 to about 2.8, an A-B permeability coefficient in the presence of a P-gp inhibitor in the range of about 0.1 to about 2.5, a B-A permeability coefficient in the range of about 0.5 to about 20 and a tPSA in the range of about 85 to about 120.

[0108] Other embodiments of JAK inhibitors according to this invention have a concentration plasma in the range from about 10 ng/ml to about 20 ng/ml.

[0109] Additional embodiments of JAK inhibitors according to this invention have cLogP values in the range of about 0.8 to about 1.4.

[0110] Additional embodiments of JAK inhibitors in accordance with this invention have an A-B permeability coefficient in the presence of a P-gp inhibitor in the range of about 0.6 to about 1.5.

[0111] Other embodiments of JAK inhibitors according to this invention have a B-A coefficient of permeability in the range of about 0.5 to about 5.

[0112] Other embodiments of JAK inhibitors according to this invention have tPSA values in the range of about 100 to about 120.

[0113] Other embodiments of JAK inhibitors according to this invention have the following JAK inhibitor physicochemical properties: a molar mass in the range of about 300 g mol -1 to about 500 g mol -1 , various donors of hydrogen bonds in the range from about 2 to about 3, a number of hydrogen bond acceptors in the range from about 4 to about 5, and a number of spinner bonds in the range from about 3 to about 6 in addition to the plasma concentrations, cLogP values, permeability coefficients, and tPSA values described above for JAK inhibitors according to this invention.

[0114] Additional embodiments of JAK inhibitors according to this invention have a molar mass in the range of about 350 g mol-1 to about 430 g mol-1.

[0115] Other embodiments of JAK inhibitors in accordance with this invention have a number of rotatable linkages that is in the range of about 5 to about 6.

[0116] In methods of treatment according to the disclosure, an effective amount of at least one active agent according to the disclosure is administered to a subject suffering from or diagnosed with such disease, disorder or medical condition. An "effective amount" means an amount or dose sufficient to generally produce the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. The effective amounts or doses of the active agents of the present disclosure can be determined by routine methods such as modelling, dose escalation studies or clinical trials, and taking into consideration routine factors, for example, the mode or route of administration or delivery of the drug, the pharmacokinetics of the agent, the severity and course of the disease, disorder or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician . For a 70 kg human, an illustrative range for a suitable dosage amount is about 1 to 1000 mg/day in single or multiple dosage units.

[0117] New JAK inhibitors are embodiments of this invention as active substances for the prevention and/or control of excessive inflammatory response and whose systemic effects are eliminated or reduced. Other embodiments of this invention are JAK inhibitors with local effects on gastrointestinal tissues for the treatment of conditions such as, but not limited to, IBD, without causing systemic effects or with acceptably reduced systemic effects.

[0118] Embodiments of this invention are low permeability JAK inhibitors. Other embodiments of this invention are JAK inhibitors that have aqueous solubility.

[0119] Once improvement of the patient's disease, disorder or condition has occurred, the dosage may be adjusted for preventive or maintenance treatment. For example, the dosage or the frequency of administration, or both, can be reduced depending on the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if the symptoms have been alleviated to an appropriate level, the treatment can be discontinued. However, patients may require long-term intermittent treatment for any recurrence of symptoms.

[0120] Furthermore, the compounds of the invention are intended for use alone, in combination with one or more other compounds of this invention, or in combination with additional active ingredients in the treatment of the conditions discussed below. Additional active ingredients may be co-administered separately with at least one compound of the invention, with active agents of the disclosure, or included with such agent in a pharmaceutical composition according to the disclosure. In an illustrative embodiment, additional active ingredients are those known or found to be effective in the treatment of conditions, disorders, or diseases mediated by JAK activity, such as another JAK inhibitor or a compound active against another target. associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy ( eg, by including in the combination a compound that enhances the potency or efficacy of an agent according to the invention), decrease one or more side effects, or decrease the required dose of the agent. active according to the invention.

[0121] When referring to inhibition of the target, an "effective amount" means an amount sufficient to affect the activity of at least one of the JAK family of proteins. Measurement of target activity can be done by routine analytical methods. Target inhibition is found in a variety of settings, including various assays.

[0122] The active agents of the invention, alone or in combination with one or more additional active ingredients, are envisioned for use in formulating the pharmaceutical compositions of the disclosure. A pharmaceutical composition of the disclosure comprises an effective amount of at least one active agent according to the invention.

[0123] Pharmaceutically acceptable excipients that are commonly used in pharmaceutical compositions are substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a drug composition. or otherwise used as a carrier or diluent to facilitate delivery of and compatibility with an agent. Examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0124] Pharmaceutical composition dosage forms containing one or more dosage units of the active agents can be prepared using pharmaceutically acceptable excipients and compounding techniques known or available to those skilled in the art. The compositions can be administered in the methods of the invention by a suitable route of administration, for example, orally, parenterally, rectally, topically or ocularly, or by inhalation.

[0125] The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations or suppositories. The compositions can be formulated for any of a number of routes of administration, such as intravenous infusion, topical administration, or oral administration. Preferably, the compositions can be formulated for oral administration.

[0126] For oral administration, the active ingredients of the invention may be provided in the form of tablets or capsules, or as a solution, emulsion or suspension. To prepare the oral compositions, the active agents may be formulated to produce a dosage of, for example, for a 70 kg human, an illustrative range for a suitable dosage amount is from about 1 to 1000 mg/day in dosage units. single or multiple.

[0127] Oral tablets may include the active ingredients admixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents, and preserving agents. Suitable inert fillers include sodium calcium carbonate, sodium calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of liquid oral carriers include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are examples of disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, can be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or they may be coated with an enteric coating.

[0128] Capsules for oral administration include hard and soft gelatin or (hydroxypropyl)methylcellulose capsules. To prepare hard gelatin capsules, the active ingredients may be mixed with a solid, semisolid, or liquid diluent. Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle prior to use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients such as suspending agents (for example, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and the like); non-aqueous vehicles, eg oil (eg almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (for example, methyl or propyl phydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0129] The active agents of this invention may also be administered by non-oral routes. For example, the compositions can be formulated for rectal administration as a suppository, enema, or foam. For parenteral use, including intravenous, intramuscular, intraperitoneal or subcutaneous routes, the agents of the invention may be provided in sterile, aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. These forms may be in unit dose form, such as ampoules or disposable injection devices, in multi-dose forms, as vials from which the appropriate dose can be withdrawn, or in a solid or pre-concentrated form that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 mg/kg/minute of agent mixed with a pharmaceutical carrier for a period ranging from several minutes to several days.

[0130] For topical administration, the agents may be mixed with a pharmaceutical carrier at a concentration of about 0.01% to about 20% drug per carrier, preferably 0.1% to 10%. Another mode of administering the agents of the invention may use a patch formulation to affect transdermal delivery.

[0131] The active agents may alternatively be administered in the methods of this invention by inhalation, nasally, or orally, eg, in a spray formulation also containing a suitable carrier.

[0132] In another aspect, the disclosure relates to a method of treating a subject suffering from or diagnosed with a JAK-mediated disease, disorder or medical condition, comprising administering to the subject in need of such treatment an effective amount of the active agent.

[0133] In certain embodiments of the inventive method, the disease, disorder or medical condition is an inflammatory bowel disease, such as Crohn's disease and ulcerative colitis.

[0134] Other aspects of this disclosure provide a method of modulating JAK activity, including when said kinase is in a subject, comprising exposing JAK to an effective amount of at least one compound selected from the compounds of the invention.

[0135] The compounds of the invention are useful as JAK inhibitors that can be orally dosed and specifically distributed to intestinal tissue while maintaining low systemic exposures. This is in contrast to most known JAK inhibitors which are orally dosed and distributed to many tissues due to the fact that they have extensive systemic exposure.

[0136] Table 1a and Table 1b show the results of in vivo experiments. These results comprise plasma and colon tissue concentrations for fifteen compounds that had been administered to mice as described in Protocols 1, 2, or 3. Plasma and colon concentration results were obtained following Protocol 1 using venipuncture of bleeding from the dorsal metatarsal vein for Compounds (B), (C) and Examples 10 and 74. Plasma and colon concentration results were obtained following Protocol 2 using retroorbital bleeding for Compounds (A), and Examples 1 and 3-5 and Protocol 2 using venipuncture of the dorsal metatarsal vein for Examples 2, 22, 34, 38, 55 and 85. The results of Protocols 1 and 2 are shown in Table 1a. Plasma and colon concentration results were obtained by following Protocol 3 for Examples 1, 3 and 4. Results from Protocol 3 are shown in Table 1b. These protocols are described below under the heading In vivo studies.

Table 1a. Results of in vivo experiments after p.o. - Average concentration of test compounds

(continuation)

Table 1b. Results of in vivo experiments after i.c. dosing: mean concentration of test compounds

[0137] Compounds (A)-(C) are the following reference compounds that have been disclosed in WO2013/007765 or WO2011/086053 for use as inhibitors of Janus kinases:

[0138] Compounds Ex. 1-5, 10, 22, 34, 38, 55, 74 and 85 in Tables 1a and 1b are embodiments of this invention given in the respective Examples.

[0139] As shown in Table 1a, concentrations in the colon for compounds Ex. 1-5, 10, 22, 34, 38, 55, 74 and 85 were much higher than the respective plasma concentrations, with proportions of concentration [colon (4 h)]: [plasma (0.5 h)] ranging from about 52 to about 3,000. In contrast, such ratios for compounds (A)-(C) ranged from about 3 to about 17. Table 1b also provides supporting data that Examples 1, 3, and 4 have low systemic exposures after i.c. dosing. The contrast between the properties of some embodiments of this invention with respect to the reference compounds is much more accentuated when the comparison refers to the 4-h plasma concentration values. In this regard, the [colon (4 h)]: [plasma (4 h)] concentration ratios for compounds Ex. 1-5, 10, 22, 34, 38, 55, 74 and 85 range from 888 to 6886. On the contrary, said ratios for compounds (A)-(C) range from 11 to 538. These two points Concentration ratios to plasma are indicative of compounds Ex. 1-5, 10, 22, 34, 38, 55, 74 and 85 have low systemic effects at any time after the oral dose, while compounds (A)-(C) have comparatively high systemic effects. This is an unexpected finding of local GI effects for compounds 1-5, 10, 22, 34, 38, 55, 74, and 85.

[0140] As shown in Table 4, the data provided therein for compounds Ex. 1-209 and (A)-(C) demonstrate inhibition of enzyme activity for all JAK proteins by these compounds.

[0141] There is no known reference teaching or suggestion that the marked lack of systemic effects for some embodiments of this invention compared to those of reference compounds (A)-(C) can be inferred and/or predict on the basis of structural comparisons. Rather, one would consider that some embodiments of this invention exhibit similar systemic effects to reference compounds (A)-(C) in light of the structural similarities that can be found by comparing the respective chemical structures.

[0142] Furthermore, there is no known reference teaching or suggestion indicating that the low permeability characteristic for some embodiments of this invention compared to those of reference compounds (A)-(C) can be inferred and/or or predict on the basis of structural comparisons. Rather, some embodiments of this invention that exhibit similar low permeability characteristics as reference compounds (A)-(C) would be considered in light of the structural similarities that can be found by comparing the chemical structures. respective.

[0143] The following specific examples are provided to further illustrate the invention and various embodiments.

[0144] To obtain the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated. Abbreviations and acronyms used in this document include the following:

Defined abbreviations and acronyms

[0145]

(continuation)

(Continuation)

[0146] Illustrative compounds useful in the methods of this disclosure are described below with reference to illustrative synthetic schemes ("Schemes") and specific examples for their preparation. One of ordinary skill in the art will recognize that, to obtain the various compounds herein, the starting materials can be suitably selected so that the ultimately desired substituents are carried through the reaction scheme with or without protection, as appropriate, to produce the desired product. Alternatively, it may be necessary or desirable to employ, in place of the ultimately desired substituent, a suitable group that can be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, variables are as defined above with reference to Formula I or Formula II. If the temperature or temperature range is not indicated, it is to be understood that the reaction must be carried out at room temperature. The schemes given below describe the general preparation procedures. The term PG is used in the Schemes to represent a protecting group such as benzene sulfonyl, 4-bromobenzene sulfonyl, or 4-methylbenzene sulfonyl. These groups are removed from the compounds in various steps and the conditions used to remove these protecting groups are deprotection including (i) treatment with a strong base, such as KOH, in a solvent such as dioxane; (ii) treating with a strong acid, such as HBr in acetic acid; or (iii) treating with sodium naphthalide in THF. In the above examples, these deprotection conditions will be referred to as "benzenesulfonyl type group deprotection conditions".

[0147] As shown in Scheme 1, compound V is converted to compound VI via reduction of the nitro group. This reduction can be achieved through a variety of methods including catalytic hydrogenation conditions such as H ² gas and a catalytic amount of a metal catalyst such as Pd or Pt, where the Pd and Pt used can be 5-10%. of Pd on carbon and 5-10 % Pt on carbon, respectively. This reduction can be carried out in a conventional manner in a flask in which the atmosphere above the reaction mixture is H ² gas or in which H ² gas is bubbled through the solution. Alternatively, the reaction can be carried out via a continuous flow hydrogenation reactor. The nitro group can also be reduced with Fe, Zn, or SnCl ² in solvents such as methanol, ethanol, isopropanol, or THF. Compound VI is converted to compound VII via a condensation reaction with ethyl 3-ethoxy-3-iminopropanoate (structure not shown) in a solvent such as ethanol, methanol, or isopropanol at about reflux temperature of solvent for a time of about 1 to 12 hours. Compound VII is converted to compound VIII by treatment with a base such as NaOH or KOH in a solvent such as methanol, ethanol or tetrahydrofuran or a mixture of said solvents. Compound VII is converted to compound IX through a two-step process, where the first step is a transamination reaction where compound VII is reacted with compound XL in a solvent such as DMF or DMA, and heated. at a temperature of about 50°C to 125°C, for 1-12 hours. This reaction can be carried out using conventional heating or carried out in a microwave reactor and NH ⁴ NO ³ can be added as a catalyst. In the second step of this two-step process, the PG is removed to provide compound IX and the conditions for this are dependent on the PG being used. When the PG is benzene sulfonyl, 4-bromobenzene sulfonyl, or 4-methylbenzene sulfonyl, then the PG is removed using the benzene sulfonyl-type group deprotection conditions. Compound VIII is converted to compound IX by reacting with compound XL and an appropriate activating reagent, for example (i) a carbodiimide, such as DCC, (ii) EDCI optionally in the presence of HOBt and/or a catalyst such as DMAP, (iii) a halotrisaminophosphonium salt such as BOP, PyBOP or PyBroP, and (iv) a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or other suitable coupling agent such as HBTU, HATU, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®), in a suitable solvent such as as DCM, THF or DMF, optionally in the presence of a tertiary amine such as N-methylmorpholine, diisopropylethyl amine or triethylamine, at a temperature ranging from about 0 °C to rt.

[0148] As shown in Scheme 2, compound V is converted to compound XIII through a condensation reaction in which compound V, ethyl glyoxalate (structure not shown) and a reducing agent such as hydrosulfite sodium [CAS# 7775-14-6], are reacted in a solvent mixture wherein the solvent mixture comprises at least two of the following solvents: DMSO, methanol, and water, at a temperature of about 100 °C for a time ranging from 1 to 18 hours. Compound V is converted to compound XII by treatment with 1,4-dioxane-2,5-diol (structure not shown), a reducing agent such as sodium hydrosulfite, in a mixed solvent where the mixed solvent it comprises at least two of the following solvents: DMSO, methanol and water, at a temperature of approximately 100 °C for a time ranging from 1 to 18 hours. Compound V is converted to compound X by reaction with ferrc-butyl (2-oxoethyl)carbamate (structure not shown), a reducing agent such as sodium hydrosulfite, in a mixed solvent where the mixed solvent comprises at least two of the following solvents: DMSO, methanol and water, at a temperature of about 100 °C for a period of 1-18 hours. Compound X is converted to compound XI by treatment with (i) 1.0 M to 4.0 M HCl in dioxane or ethyl acetate, where the reaction solvent is CH ² Cl ² or ethyl acetate or (ii) TFA in CH ² Cl ² . In these cases, it is understood that compound XI is produced as a hydrochloride salt or a trifluoroacetate salt. Alternatively, other acids could be used to convert compound X to compound XI, and it is understood that the salt form of compound XI would reflect the acid used. Compound X is converted to compound II using benzenesulfonyl-type group deprotection conditions, and compound II is converted to compound IV by treatment with an acid such as 1.0 M to 4.0 M HCl in dioxane. .

[0149] As described in Scheme 3, compound VI is converted to compound XVI by treatment with 2-chloro-1,1,1-triethoxyethane (structure not shown) in acetic acid at a temperature of approximately 125 °C. . Compound XII is converted to compound XVI by treatment with thionyl chloride, in a solvent such as CH ² Cl ² , dichloroethane or chloroform. Compound VI is converted to compound XV in a two-step reaction in which, in the first step, compound VI is treated with Ar-CH ² -CO ² H, with an appropriate activating reagent, for example (i ) a carbodiimide, such as DCC, (ii) EDCI optionally in the presence of HOBt and/or a catalyst such as DMAP, (iii) a halotrisaminophosphonium salt such as BOP, PyBOP or PyBroP, and (iv) a suitable pyridinium salt such as 2- chloro-1-methylpyridinium chloride; or other suitable coupling agent such as HBTU, HATU, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®), in the presence of a base such as TEA, DIPEA or pyridine in a solvent such as DMF, DMA or DMSO. In the second step of the two-step process, the resulting amide intermediate (structure not shown) is cyclized to form compound XV by treating it with an acid such as acetic acid at a temperature of about 100°C for 1-18 hours. Compound XV is converted to compound XVII by deprotection of the PG. When the PG is benzene sulfonyl, 4-bromobenzene sulfonyl, or 4-methylbenzene sulfonyl, this group is removed using the benzene sulfonyl-type group deprotection conditions.

[0150] Compound XVI with certain R14 assignments is transformed into compound XVIII as illustratively described in processes (a) and (b) below.

(a) When compound XVIII is desired in the form in which R14 is a substituted or unsubstituted phenyl, then compound XVI is reacted with the appropriately substituted phenol (structure not shown) in a solvent such as DMF, DMA or THF, with a base such as NaOH, KOH, CS ² CO ³ or K ² CO ³ and KI at 50 °C to 80 °C for 1-12 hours.

(b) When compound XVIII in the form in which R14 is ^C1 - ^C6 alkyl is desired, then compound XVI is treated with R14ONa or R14OK where R14 is ^C1 - ^C6 alkyl, in a solvent such as R14OH or THF.

[0151] When compound XLII in the form in which R10 is ^C1 - ^C6 alkyl, ^C3 - ^C10 cycloalkyl, phenyl, benzyl, pirazolyl is desired, then compound XVI is treated with compound XLI in a solvent such as DMF, DMA or THF with a base such as NaOH, KOH, CS ² CO ³ or K ² CO ³ , for a period of between 1-12 hours.

[0152] Compound XVI is converted to compound XIX by treatment with compound XXXVI and a base such as NaOH, KOH, CS ² CO ³ or K ² CO ³ in a solvent such as DMF, DMA or THF for a period of between 1 -12 hours.

[0153] Compound XVI is converted to compound XXVIII by treating it with sulfoximine (XXXV) in the presence of a base such as NaHCO3 or K ² CO ³ in a solvent such as THF or CH ³ CN.

[0154] As shown in Scheme 5, when compound XXI is desired in the form in which R1 is an optionally substituted phenyl group, an optionally substituted 5-6 membered heteroaromatic ring, an optionally substituted C ⁴ -C ⁷ heterocyclic ring substituted o-(CH2)q-(OCH2CH2)qOCH3 then compound V is treated with the appropriately substituted aldehyde and a reducing agent such as Na ² S ² O 4 in a solvent mixture of at least two of the following solvents: DMSO, methanol and water, at a temperature of about 100 °C for a time ranging from 1 to 18 hours. In cases where the protecting group is not removed when using the above conditions, this protecting group is removed using the benzenesulfonyl type group deprotection conditions.

[0155] When compound XXXVIII is desired in the form in which R10 is -CH ² -cyclohexyl, -CH(CH3)2 and -phenyl, compound XI undergoes a two-step process. In the first step, compound XI is reacted with compound XXXIX in a solvent such as DMF, DMA, or DMSO in the presence of a base such as trimethylamine, DIPEA, or pyridine. In the second step, the PG is removed by treating it with a base such as aqueous KOH or aqueous NaOH in a solvent such as dioxane with heating at a temperature of approximately 50-100 °C, for 1-10 hours.

[0156] When compound XVIII is desired in the form in which R14 is

Compound XII, is treated with the appropriately substituted isocyanate, in a solvent such as DMF or DMA, in the presence of a base such as trimethylamine or diisopropylethylamine, in which the reaction can be carried out at room temperature or can be heated to a temperature of about 60 °C to 100 °C for a period of time ranging from 0.25 hours to 72 hours. The final step of this transformation is the removal of PG. When the PG is a benzenesulfonyl group, it is removed by treating it with a base such as aqueous KOH or aqueous NaOH in a solvent such as dioxane with heating at a temperature of about 50-100°C for 1-10 hours.

[0157] Scheme 8 describes the synthesis of compound XXVII (Intermediate 9). Compound XXIII is converted to compound XXIV by treating compound XXIII with a reducing agent such as a borane/THF complex in a solvent such as THF or ether. Other suitable reducing agents include BH3/Me2S complex or NaBH4/BF3 etherate. Compound XXIV is converted to compound XXV by treatment with mesyl chloride in a solvent such as CH ² Cl ² or THF in the presence of a base such as pyridine, trimethylamine, or DIPEA at 0°C to room temperature. One of ordinary skill in the art will recognize that many different leaving groups can be prepared in place of the mesylate, including triflate and tosylate. Compound XXV is converted to Compound XXVI by treatment with NaCN or KCN in a solvent such as DMSO, DMF, or DMA at a temperature ranging from room temperature to about 125°C for about 18 hours. Compound XXVI is converted to compound XXVII by treatment with (i) 1.0 M to 4.0 M HCl in dioxane or ethyl acetate, where the reaction solvent is CH ² Cl ² or ethyl acetate or (ii) TFA in CH ² Cl ² .

[0158] When compound XLIII in the form in which one of R4 and R5 is H and the other is SO ² R6 is desired, compound IV is treated with an appropriately substituted sulfonyl chloride, in a solvent such as CH ² Cl ² , THF or DMF, in the presence of a base such as TEA, DIPEA, NMO or pyridine.

[0159] When compound XX is desired in the form in which R9 is N-OH and R10 is ^C1 - ^C6 alkyl, ^C2 - ^C3 alkyl ether, ^C3 - ^C10 cycloalkyl, phenyl or benzyl compound IV is Treat with the appropriately substituted chloroximine in a solvent such as DMF or DMA in the presence of a base such as TEA, DIPEA, pyridine, or NMO.

[0160] When compound XX in the form in which R9 is O and R10 is O-C ¹ -C ⁶ alkyl or O-phenyl is desired, compound IV is treated with the appropriately substituted chloroformate or anhydride in a solvent such as CH ² Cl ² or THF in the presence of a base such as TEA, DIPEA, pyridine, or NMO.

[0161] When compound XX is desired in the form in which R9 is O and R10 is ^C1 - ^C6 alkyl, ^C3 - ^C10 cycloalkyl, phenyl, benzyl, or 5-membered heteroaryl, compound IV is treated with the appropriately substituted carboxylic acid and an activating agent such as a carbodiimide, such as DCC or EDCI optionally in the presence of HOBt and/or a catalyst such as DMAP; a halotrisaminophosphonium salt such as PyBroP; a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or other suitable coupling agent such as BOP, PyBOP, HBTU, HATU, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®) in a suitable solvent such as DCM, tHf , dMf , optionally in the presence of a tertiary amine such as N-methylmorpholine, diisopropylethylamine or triethylamine, at a temperature ranging from about 0 °C to rt. Alternatively, compound IV is treated with the appropriately substituted acid chloride or acid anhydride. This reaction can be carried out in a solvent such as CH ² Cl ² , THF or DCM in the presence of a base such as TEA, DIPEA, pyridine or NMO.

[0162] When compound XX in the form in which R9 is O and R10 is ^NH2 is desired, compound IV is treated with KOCN [CAS# 590-28-3] in water in the presence of a base such as NaHCO3 at a temperature ranging from room temperature to reflux temperature for a period of time between 15 min and 24 hours.

[0163] Scheme 10 illustrates the preparation of compound XXXIV. Compound XXVII is converted to compound XXX upon treatment with compound XXIX, in a solvent such as methanol, ethanol, or isopropanol, in the presence of a base such as TEA, DIPEA, pyridine, or NMO, at room temperature to room temperature. reflux temperature. of the solvent and for a period of time between 1 hour and 24 hours. Compound XXX is converted to compound XXXI through reducing conditions including catalytic hydrogenation conditions such as H ² gas and a catalytic amount of a metal catalyst such as Pd or Pt, where the Pd and Pt used may be 5 -10% Pd on carbon and 5 -10% Pt on carbon, respectively. This reduction can be carried out in a conventional manner in a flask in which the atmosphere above the reaction mixture is H ² gas or in which H ² gas is bubbled through the solution. Alternatively, the reaction can be carried out via a continuous flow hydrogenation reactor or using zinc dust in the presence of NH4Cl and EtOH. Other reaction conditions include iron in acetic acid; and sodium dithionate in DMSO, methanol and water. Compound XXXI is converted to compound XXXII by a reaction with ethyl 3-(ethoxyimino)propanoate hydrochloride (structure not shown), in a solvent such as methanol, ethanol or isopropanol, at a temperature between room temperature and the reflux temperature of the solvent for a period of time between 1 hour and 48 hours. When compound XXXIV where RA is C(O)NH ² is desired, then compound XXXII is treated with aqueous NH ⁴ OH in a solvent such as THF. The resulting compound is then subjected to benzene sulfonyl-type group deprotection conditions as discussed above. Compound XXXII is converted to compound XXXIII by treatment with a base such as NaOH or KOH in a solvent or a mixture of the following solvents: methanol, ethanol, isopropanol, THF, and ether. When compound XXXIV is desired in the form in which Ra is one of the following:

then compound XXXIII is treated with the appropriately substituted amine (structure not shown), an activating reagent, for example a carbodiimide, such as DCC or EDCI optionally in the presence of HOBt and/or a catalyst such as DMAP; a halotrisaminophosphonium salt such as BOP, PyBOP or PyBroP; a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or other suitable coupling agent such as HBTU, HATU, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®). Coupling reactions are carried out in a suitable solvent such as DCM, THF, or DMF, optionally in the presence of a tertiary amine such as N-methylmorpholine, diisopropylethylamine, or triethylamine, at a temperature ranging from about 0°C to rt.

When compound XXXIV in the form in which X is Cl is desired, compound XXXV is treated with a chlorinating agent such as 2-chloro-1,3-bis(methoxycarbonyl)guanidine or NCS in a solvent such as CH ³ CN in the presence of from a base such as NaHCO3, CS ² CO ³ . When compound XXXIV in the form in which X is Br is desired, compound XXXV is treated with NBS in a solvent such as dioxane. When Compound XXXIV in the form in which X is methyl is desired, then Compound XXXIV in the form in which X is Br is treated with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, (2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) and dimethyl zinc in a solvent such as THF , at a temperature of approximately 75 - 85 °C for a period of time between 15 min and 3 hours.

[0164] Compounds of the invention can be converted to their corresponding salts using methods described in the art. For example, a compound of the invention is treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as Et ² O, CH ² Cl ² , THF, MeOH, or isopropanol to provide the corresponding salt form. Crystalline forms of the pharmaceutically acceptable salts of the compounds of the invention may be obtained in crystalline form by recrystallization from polar solvents (including polar solvent mixtures and aqueous polar solvent mixtures) or from nonpolar solvents (including nonpolar solvent mixtures). polar).

[0165] The following examples are provided to further illustrate aspects of the disclosure and various preferred embodiments. The invention is defined by the claims.

[0166] To obtain the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0167] Unless otherwise indicated, reaction mixtures were stirred magnetically at room temperature (rt). When solutions are "dried", they are usually dried over a drying agent such as Na2SO4 or MgSO4. When the mixtures, solutions and extracts are "concentrated", they are usually concentrated on a rotary evaporator under reduced pressure.

[0168] Thin layer chromatography was performed using Merck Silica Gel 60 F ²⁵⁴ 2.5 cm X 7.5 cm, 250 gm or 5.0 cm X 10.0 cm, 250 gm pre-coated silica gel plates .

[0169] Normal phase flash column chromatography (FCC) was performed on silica gel (SiO ² ) eluting with MeOH/CH ² Cl ² (0-10%), unless otherwise indicated.

[0170] Mass spectra (MS) were obtained on an Agilent 1100 series MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. The calculated mass (calc.) corresponds to the exact mass.

[0171] High performance liquid chromatography was performed as described for individual compounds. The next capped columns used were Varian Pursuit XRs5 Diphenyl (100 A pore size, 440 m2/g surface area, 14.6% carbon loading), Waters Xbridge Prep OBD C ¹⁸ (130 A pore size, 185 m2/g surface area, 18% carbon load), Boston Green ODS (100 A pore size, 450 m2/g surface area, 21.7% carbon load), Kromasil, (185 m2/g surface area, 21.7% carbon load), 100 Á, 340 m2/g surface area, 19% carbon load), Agela DuraShell (150 Á pore size, 380 m2/g surface area, 21% carbon load), Xtimate C ¹⁸ , (size 200 A pore size, 320 m2/g surface area, 14% carbon loading, Diamonsil (100 A pore size, 440 m2/g surface area, 17% carbon loading), Phenomenex Luna C ¹⁸ , (100 A pore size, 440 m2/g surface area, 19% carbon loading), Phenomenex Synergi C ¹⁸ (100 A pore size, 475 m2/g surface area, 11-19% carbon loading ) and Phenomenex Gemini (pore size 110 Á , surface area 375 m2/g, carbon load of 14%).

[0172] Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers. The format of the 1 H NMR data below is: chemical shift in ppm downfield from the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).

[0173] Chemical names were generated using ChemDraw (CambridgeSoft, Cambridge, MA) or ACD/Name Version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).

[0174] To provide a more concise description, some of the quantitative expressions provided in this document are not qualified by the term "approximately". It is understood that, whether the term "approximately" is used explicitly or not, each quantity given in this document refers to the actual value given, and also refers to the approximation to such value given that would be reasonably inferred based on skill. common in the art, including equivalents and approximations due to experimental and/or measurement conditions for said given value.

[0175] Whenever a yield is given in percentage, said yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Reagent concentrations given as percentages refer to mass proportions, unless otherwise indicated.

Synthesis and characterization of intermediate 1:

2-((7r,4r)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile

[0176]

[0177] Step A: tert-butyl N-[(1r,4r)-4-(Hydroxymethyl)cyclohexyl]carbamate. (1r,4r)-4-[[(tert-butoxy)carbonyl]amino]cyclohexane-1-carboxylic acid (1066 g) was placed in a 20 L 4-necked round bottom flask, purged and maintained under an inert atmosphere of nitrogen. , 4.38 mol, 1.00 equiv) and THF (10 L). This was followed by the dropwise addition of BH3-Me2S (10 M, 660 mL) at -10 °C for 1 h. The resulting solution was stirred for 3 h at 15 °C. This reaction was run three times in parallel and the reaction mixtures were combined. The reaction was then quenched by the addition of methanol (2 L). The resulting mixture was concentrated in vacuo. This resulted in ferc-butyl N-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]carbamate (3000 g, 99.6%) as a white solid. MS (ESI): mass calc. for C ¹² H ²³ NO ³ , 229.32; m/z found, 215.2 [M-tBu+MeCN+H]+; 1H NMR: (300 MHz, CDCls): 54.40 (s, 1H), 3.45 (d, J= 6.3 Hz, 2H), 3.38 (s, 1H), 2.05-2, 02 (m, 2H), 1.84-1.81 (m, 2H), 1.44 (s, 11H), 1.17-1.01 (m, 4H).

[0178] Step B: Ferc-butyl N-[(1r,4r)-4-[(Methanesulfonyloxy)methyl]cyclohexyl]carbamate. Tert-Butyl N-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]carbamate (1000 g, 4.36 mol, 1.00 equiv.), dichloromethane (10 L), pyridine (1 ^{3 8 0} g, 17.5 mol, 4.00 equiv.). This was followed by the dropwise addition of MsCl (1000 g, 8.73 mol, 2.00 equiv) at -15 °C. The resulting solution was stirred overnight at 25 °C. This reaction was run in parallel 3 times and the reaction mixtures were combined. The reaction was then quenched by adding 2 L of water. The aqueous phase was extracted with ethyl acetate (1 x 9 l). The organic layer was separated and washed with 1M HCl (3 x 10 L), NaHCO ³ (aq saturated) (2 x 10 L), water (1 x 10 L, and brine (1 x 10 L). The mixture was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo This gave ferrc-butyl n-[(1r,4r)-4-[(methanesulfonyloxy)methyl]cyclohexyl]carbamate (3300 g, 82%) as a white solid LC-MS: MS (ESI): mass calculated for C ¹³ H ²⁵ NO ⁵ S, 307.15, m/z found 292.1, [MfBu +MeCN+H]+, 1H NMR: (300 MHz, CDCla): 54.03 (d, J = 6.6 Hz, 2H), 3.38 (s, 1H), 3.00 (s, 3H), 2.07-2.05 (m, 2H ), 1.87-1.84 (m, 2H), 1.72-1.69 (m, 1H), 1.44 (s, 9H), 1.19-1.04 (m, 4H).

[0179] Step C: ferrt-butyl N-[(1 r,4r)-4-(cyanomethyl)cyclohexyl]carbamate. Tert-Butyl W-[(1r,4r)-4-[(methanesulfonyloxy)methyl]cyclohexyl]carbamate (1100 g, 3.58 mol, 1.00 equiv.), DMSO (5500 mL) and NaCN (406 g, 8.29 mol, 2.30 equiv.). The resulting mixture was stirred for 5 h at 90 °C. This reaction was run in parallel 3 times and the reaction mixtures were combined. The reaction was then quenched by adding 15 L of ice/water. The solids were collected by filtration. The solids were washed with water (3 x 10 L). This resulted in ferc-butyl n-[(1r,4r)-4-(cyanomethyl)cyclohexyl]carbamate (2480 g, 97%) as a white solid. MS (ESI): mass calc. for C ¹³ H ²² N ² O ² , 238.17; m/z found 224 [M- f Bu+MeCN+H]+; 1H NMR: (300 MHz, CDCl3): 54.39 (s, 1H), 3.38 (s, 1H), 2.26 (d, J =6.9 Hz, 2H), 2.08-2, 04 (m, 2H), 1.92-1.88 (m, 2H), 1.67-1.61 (m, 1H), 1.44 (s, 9H), 1.26 1.06 (m , 4H).

[0180] Step D: 2-[(1r,4r)-4-aminocyclohexyl]acetonitrile hydrochloride. Ferc-butyl W-[(1r,4r)-4-(cyanomethyl)cyclohexyl]carbamate (620 g, 2.60 mol, 1.00 equiv) and 1, were placed in a 10 L round bottom flask. 4-dioxane (2L). This was followed by the addition of a solution of HCl in 1,4-dioxane (5 L, 4 M) dropwise with stirring at 10 °C. The resulting solution was stirred overnight at 25 °C. This reaction was run 4 times and the reaction mixtures were combined. The solids were collected by filtration. The solids were washed with 1,4-dioxane (3 X 3 L), ethyl acetate (3 X 3 L), and hexane (3 X 3 L). This resulted in 2-[(1r,4r)-4-aminocyclohexyl]acetonitrile hydrochloride (1753 g, 96%) as a white solid. MS (ESI): mass calc. for C ⁸ H ¹⁴ N ² , 138.12; m/z found 139.25, [M+H]+; 1H NMR: (300 MHz, DMSO-d6): 8.14 (s, 3H), 2.96-2.84 (m, 1H), 2.46 (d, J = 6.3 Hz, 2H) , 1.98 (d, J = 11.1 Hz, 2H), 1.79 (d, J = 12.0 Hz, 2H), 1.64-1.49 (m, 1H), 1.42- 1.29 (m, 2H), 1.18-1.04 (m, 2H).

[0181] Step E: 2-((1r,4r)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile . To a 1000 mL round bottom flask containing 2-[(1r,4r)-4-aminocyclohexyl]acetonitrile hydrochloride (29.10 g, 166.6 mmol) was added DMA (400 mL). The resulting suspension was treated with 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (51.53 g, 152.6 mmol), followed by DIPEA (63.0 ml, 366mmol). The reaction mixture was placed under N ² and heated at 80 °C for 4 h. The crude reaction mixture was cooled to room temperature and slowly poured into a vigorously stirred 2 L flask containing 1.6 L of water. The resulting suspension was stirred for 15 min at room temperature, then filtered and dried for 16 h in a vacuum oven heated to 70 °C to give the title compound (63.37 g, 95%) as a solid. yellow. MS (ESI): mass calc. for C ²¹ H ²¹ N ⁵ O ⁴ S, 439.1; m/z found, 440.1 [M+H]+. 1H NMR (500 MHz, CDCla): 59.10 (s, 1H), 8.99 (d, J = 7.8 Hz, 1H), 8.23-8.15 (m, 2H), 7.66 -7.59 (m, 2H), 7.56 - 7.49 (m, 2H), 6.67 (d, J = 4.2 Hz, 1H), 3.95 - 3.79 (m, 1H ), 2.38 (d, J = 6.2 Hz, 2H), 2.32 - 2.21 (m, 2H), 2.08-1.98 (m, 2H), 1.88-1, 76 (m, 1H), 1.60-1.32 (m, 4H).

Synthesis and characterization of the intermediate

2: 2- (( 1r,4r)-4- (( 5-Amino-1- ( phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile

[0182]

[0183] 2-(( 1r,4r)-4-((5-Nitro-1 -(phenylsulfonyl)-l H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1.58.60 g, 133.3 mmol) was dissolved in THF/MeOH (1:1.4800 mL). The mixture was passed through a continuous flow hydrogenation reactor (10% Pd/C), such as a Thales Nano H-Cube®, at 10 mL/min with 100% hydrogen (atmospheric pressure, 80 °C), then the solution was concentrated. to provide the product as a purple solid. The solid was triturated with EtOAc (400ml) then triturated again with MeOH (200ml), then filtered and dried in vacuo to give the title compound (50.2g, 91.9% yield). MS (ESI): mass calc. for C ²¹ H ²³ N ⁵ O ² S, 409.2; m/z found, 410.2 [M+H]+.

1H NMR (400 MHz, CDCla) 58.10 - 8.03 (m, 2H), 7.76 (s, 1H), 7.51 - 7.43 (m, 1H), 7.43 - 7.34 (m, 3H), 6.44 (d, J = 4.2 Hz, 1H), 4.61 (d, J = 8.5 Hz, 1H), 3.65 - 3.51 (m, 1H) , 2.74 (s, 2H), 2.26 (d, J = 6.4 Hz, 2H), 2.19-2.05 (m, 2H), 1.97-1.86 (m, 2H ), 1.76-1.59 (m, 1H), 1.33-1.12 (m, 4H).

Synthesis and characterization of intermediate 3:

2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)ethyl acetate

[0184]

[0185] To a 1 L round bottom flask containing a stir bar and 2-((1 r,4r)-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3 -b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (intermediate 2, 58.31 g, 142.4 mmol) was added ethyl 3-ethoxy-3-iminopropanoate (60.51 g, 309.3 mmol) , followed by EtOH (600 mL, dried over 3A molecular sieves for 48 h). A reflux condenser was connected to the reaction flask, the reaction was purged with N ² and heated at 90 °C for 9 h. The reaction mixture was cooled to room temperature and allowed to stand for 30h until the product crystallized as brown needles. The solids were broken up with a spatula and the reaction mixture was transferred to a 2 L flask. Water (1.4 L) was added slowly through a separatory funnel with vigorous stirring. After the addition of the water was complete, the suspension was stirred for 30 minutes. The brown needles were isolated by filtration and then dried by blowing air through the filter for 1 hour. The product was transferred to a 500 mL flask and treated with EtOAc (200 mL). A small amount of seed crystals was added, which induced the formation of a white solid precipitate. The suspension was stirred for 30 minutes at room temperature, filtered, rinsed with EtOAc (25 mL) and dried in vacuo to give the product as a white solid (48.65 g, 68% yield). MS (ESI): mass calc. for C ²⁶ H ²⁷ N ⁵ O ⁴ S, 505.2; m/z found, 506.2 [M+H]+. 1H NMR (400 MHz, CDCl3) 58.85 (s, ^1h ), 8.28-8.19 (m, 2H), 7.84 (d, J =4.0 Hz, 1H), 7.61 - 7.53 (m, 1H), 7.52 - 7.43 (m, 2H), 6.84 (d, J = 4.1 Hz, 1H), 4.32 (s, 1H), 4, 20 (q, J = 7.1 Hz, 2H), 4.09 (s, 2H), 2.44 (d, J = 6.2 Hz, 2H), 2.40 - 2.27 (m, 2H ), 2.16 (d, J = 13.3 Hz, 2H), 2.12-1.96 (m, 3H), 1.54-1.38 (m, 2H), 1.27 (t, J = 7.1Hz, 3H).

Synthesis and characterization of intermediate 4:

2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3]sodium -b]pyridin-2-yl)acetate

[0186]

[0187] To a solution of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b/pyridin-2-yl)ethyl acetate (intermediate 3, 9.50 g, 18.8 mmol) in MeOH (30 mL) and THF (30 mL) was added aqueous sodium hydroxide (56.4 mL, 56 0.4 mmol, 1 M) and stirred at room temperature for 14 hours. The solvent was removed under reduced pressure at room temperature to give the title compound (7 g) as a brown solid, which was used in the next step without further purification. MS (ESI): mass calc. for C18H18N5NaO2, 359.1; m/z found, 337.9 [M+H-Na]+.

1H NMR (400 MHz, CD ³ OD) 58.52 - 8.47 (m, 1H), 7.85 - 7.81 (m, 2H), 7.46 - 7.41 (m, 4H), 6 .85 -6.81 (m, 1H), 4.60 -4.46 (m, 1H), 3.96 (s, ^2H ), 2.59 - 2.49 (m, 4H), 2, 19-2.05 (m, 6H), 1.56-1.43 (m, 2H) (a 1:1 mixture of the title compound and benzenesulfonic acid).

Synthesis and characterization of intermediate 5:

2-((1r,4r)-4-(2-(Aminomethyl)imidazo[4,5-d]pyrrolo[2,3-b/pyridin-1(6H)-yl)cyclohexyl)acetonitrile hydrochloride

[0188]

[0189] Step A: ferc-butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2, 3-b]pyridin-2-yl)methyl)carbamate and 2-((1r,4r)-4-(2-(aminomethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3 -b/pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. A solution of 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1 , 1.50 g, 3.41 mmol), tert-butyl(2-oxoethyl)carbamate (1.47 g, 7.85 mmol), sodium hydrosulfite (2.97 g, 17.1 mmol), DMSO ( 3 ml), methanol (10 ml) and water (5 ml) was stirred for 2.5 hours at 100 °C. Mixture of two products, ferc-butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methyl)carbamate and 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-d]pyrrolo[2,3-b/pyridin-1(6H)-yl)cyclohexyl )acetonitrile. The reaction mixture was used for the next step directly.

[0190] Step B: ferc-butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2, 3-fo]pyridin-2-yl)methyl)carbamate. (Boc) ² O (1.04 g, 4.78 mmol) was added to a mixture of ferc-butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)- 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b/pyridin-2-yl)methyl)carbamate and 2- (( 1r,4r)-4- ( 2- (aminomethyl)-6- (phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b/pyridin-1(6H)-yl)cyclohexyl)acetonitrile (36 mL reaction mixture, 6.826 mmol), Na2CO3 (2.17 g, 20.5 mmol), and methanol (50 mL) and stirred for 2 hours at 12 °C. The reaction was concentrated in vacuo to dryness and the aqueous layer was diluted with water (30ml) and extracted with ethyl acetate (50ml X 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to provide the title compound (2.4 g, 63% in two steps) as a light yellow solid. 1H NMR (400MHz, ^c D ^c I3): 58.83 (s, 1H), 8.23 (d, J = 7.6 Hz, 2H), 7.84 (d, J = 4.0 Hz, 1H ), 7.60 - 7.52 (m, 1H), 7.52 - 7.44 (m, 2H), 6.83 (d, J = 4.0 Hz), 1H), 5.36 (br s, 1H), 4.67 (d, J = 5.6 Hz, 2H), 4.65 -4.59 (m, 1H), 2.40 (d, J = 6.4 Hz, 2H), 2.37 - 2.22 (m, 2H), 2.20 - 2.09 (m, 2H), 2.04-1.87 (m, 3H), 1.53-1.39 (m, 11H) ).

[0191] Step C: ferc-butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)methyl)carbamate. Aqueous KOH (4.37 mL, 13.1 mmol) was added to a solution consisting of tert-butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1 ,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b/pyridin-2-yl)methyl)carbamate (2.40 g, 4.37 mmol) and dioxane (25 mL) and stirred for 2 hours at 80 °C. The reaction mixture was adjusted to pH = 7-8 with 1M HCl and volatile solvents were removed in vacuo. The aqueous phase was diluted with water (20ml) and extracted with ethyl acetate (50ml X 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to provide the title compound (2 g, 100% yield) as a light yellow solid, which was used in the next step without further purification. MS (ESI): mass calc. for C ²² H ²⁸ N ⁶ O ² , 408.2; m/z found, 409.1 [M+H]+.

1H NMR (400 MHz, DMSO-ds): 11.86 (s, 1H), 8.51 (s, 1H), 7.56-7.49 (m, 1H), 7.47 (t, J = 2.8 Hz, 1H), 6.74 -6.68 (m, 1H), 4.66 -4.58 (m, 1H), 4.53 (d, J = 5.6 Hz, 2H) , 2.58 (d, J = 5.6 Hz, 2H), 2.41 - 2.28 (m, 2H), 2.08-1.94 (m, 3H), 1.93 1.83 ( m, 2H), 1.54-1.23 (m, 11H).

[0192] Step D: 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) hydrochloride cidohexyl)acetonitrile. HCl/dioxane (10 mL, 40 mmol, 4 M) was added to a solution of ferc-butyl(( 1- (( 1r,4r)-4- (cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5 -d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate (2.0 g, 4.9 mmol) in CH ² Cl ² (20 mL) at 0 °C and stirred for 30 min at 10°C. The reaction was concentrated to dryness to provide the title compound (1.7 g, 100% yield) as a pale white solid, which was used without further purification. MS (ESI): mass calc. for C17H2üCIN6, 308.2; m/z found, 308.9 [M+H]+, 1H NMR (400 MHz, DMSO-d6) 512.53 (s, 1H), 8.88 (s, 1H), 8.86 (br. s , 3H), 7.67 (t, J = 3.2 Hz, 1H), 6.93 (s, 1H), 4.71-4.63 (m, 2H), 4.60 -4.42 ( m, 1H), 2.60 (d, J = 6.0 Hz, 2H), 2.36-2.21 (m, 2H), 2.12-1.93 (m, 5H), 1.56 -1.42 (m, 2H).

Synthesis and characterization of intermediate 6:

Ethyl 1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxylate

[0193]

[0194] A 2-((1r,47)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)ddohexyl)acetonitrile (Intermediate 1,440 mg, 1 mmol) in DMSO (2.5 mL) and H ² O (0.15 mL), ethyl glyoxalate (307 mg, 3 mmol) followed by sodium hydrosulfite (523 mg, 3 mmol). The reaction mixture was heated at 100 °C for 15 h. The reaction was cooled to room temperature. H ² O (20 mL) was added. Solids formed and collected by filtration. The solids were purified by flash column chromatography (10% acetone/ ^c H ² CI ² ) to provide 1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxylate (410 mg, 83%). MS (ESI): mass calc. for C ²⁵ H ²⁵ N ⁵ O ⁴ S, 491.16; m/z found, 492.2 [M+H]+, 1H NMR (500 MHz, CDCI ³ ) 59.02 - 8.85 (m, 1H), 8.21 - 8.08 (m, 2H), 7.90 - 7.77 (m, 1H), 7.55 - 7.46 (m, 1H), 7.47 - 7.36 (m, 2H), 6.93 -6.79 (m, 1H ), 5.58 - 5.25 (m, 1H), 4.50 -4.02 (m, 2H), 2.41 - 2.34 (m, 3H), 2.10 (d, J = 13 0.2 Hz, 2H), 2.02-1.95 (m, 2H), 1.48-1.37 (m, 2H), 1.29-1.14 (m, 5H).

Synthesis and characterization of intermediate 7:

2-((1r,4r)-4-(2-(Hydroxymethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile

[0195]

[0196] A solution of 2-((7r,4rM-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b/pyridin-4-yl)amino)cyclohexyl)acetonitrile (intermediate 1,900 mg, 2.05 mmol), 1,4-dioxane-2,5-diol (400 mg, 3.33 mmol), and sodium hydrosulfite (1.05 g, 5.12 mmol) in DMSO (6 mL ), MeOH (20 mL) and distilled water (4 mL) in a pressure tube was heated at 100 °C for 12 h.The reaction was filtered and the white solid was washed with water, MeOH and EtOAc and dried to give the title compound (654 mg, 71%).The filtrate was concentrated and water was added to form a light brown precipitate.The precipitated light brown solid was filtered, washed with water and EtOAc and dried over anhydrous MgSO4 to to provide 150 mg of a light brown solid.The filtrate from the light brown precipitate wash was extracted with EtOAc (3x) to give extracts A. Extracts A were washed with water to give aqueous layer A. to extract with EtOAc (2x) to provide extracts B. Extracts B were dried over anhydrous MgSO4, filtered, and concentrated to dryness to provide 50 mg of an oil, which was combined with the above brown solid to provide the second portion of the title compound (200 mg, 22% yield) which used as is in the next reaction without further purification. MS (ESI): mass calc. for C ²³ H ²³ N ⁵ O ³ S 449.15; m/z found, 450.1 [M+H]+, 1H NMR (400 MHz, CDCh) 5 = 8.85 (s, 1H), 8.26-8.22 (m, 2H), 7.85 (d, J =4.0 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.53 - 7.46 (m, 2H), 6.83 (d, J =4.0 Hz, 1H), 4.95 (s, 2H), 4.55 (br s, 1H), 2.44 (d, J =6.6 Hz, 2H), 2.32 (br s, 2H), 2.17 (d, J =13.6 Hz, 2H), 2.13-1.97 (m, 3H), 1.53-1.43 (m, 2H).

Synthesis and characterization of intermediate 8:

2-((7r,4r,M-(2-(Chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-a(|pyrrolo[2,3-b/pyridin-1(6Hj-yl)cyclohexyl)acetonitiyl

[0197]

[0198] A solution of 2-((7r,4r,M-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b/pyridin-4-yl)amino)cyclohexyl)acetonitrile ( Intermediate 2, 818 mg, 2.00 mmol) and 2-chloro-1,1,1-triethoxyethane (786 mg, 4.00 mmol) in acetic acid (5 mL) in 50 mL flask was placed in a bath at 125 °C and heated for 20 min. The reaction mixture was cooled, diluted with CH ² Cl ² (200 mL) and stirred over saturated sodium bicarbonate until bubbling ceased. The organic layer was collected and washed with water, brine, dried over anhydrous Na ² SO ⁴ , and concentrated to dryness The residue was purified by flash column chromatography to give the title compound (800 mg, 85% yield) MS (ESI): mass Calcd for C23H22ClN5O2S, 467.12, m/z found, 468.0 [M+H]+ 1H R ^m N (400 MHz, DMSO-afe): 58.72 (s, 1H), 8.13 ( d, J= 8.0 Hz, 2H), 7.99 (d, J= 4.0 Hz, 1H), 7.73 - 7.65 (m, 1H), 7.63 - 7.55 (m , 2H), 7.14 (d, J = 4.0 Hz, 1H), 5.19 (s, 2H), 4.65 -4.53 (m, 1H), 2.57 (d, J = 5 0.6 Hz, 2H), 2.27-2.12 (m, 2H), 2.11-1.88 (m, 5H), 1.49-1.35 (m, 2H).

Synthesis and characterization of intermediate 9:

2-(4-Aminobicyclo[2,2,2]octan-1-yl)acetonitrile hydrochloride.

[0199]

[0200] Step A: tert-butyl (4-(hydroxymethyl)bicyclo[2,2,2]octan-1-yl)carbamate. Boronotetrahydrofuran complex (22.3 mL, 22.3 mmol, 1 M) was added dropwise to a 0 °C solution of 4-((tert-butoxycarbonyl)amino)bicyclo[2,2,2]octane-1-acid -carboxylic acid (3.0 g, 11 mmol) and anhydrous THF (5 mL). The resulting mixture was stirred at room temperature for 3 hours before being slowly quenched with H ² O (10 mL) and extracted with ethyl acetate (50 mL X 3). The combined organic extracts were washed with brine (35 mL), dried over anhydrous MgSO4, filtered, concentrated to dryness under reduced pressure, and purified by flash column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give the title compound (2.8 g, 98%) as a sticky colorless oil. 1H NMR (400 MHz, DMSO-afe) 56.27 (br s, 1H), 4.28 (t, J= 5.2 Hz, 1H), 2.97 (d, J= 5.2 Hz, 1H ), 1.74 1.59 (m, 6H), 1.42-1.25 (m, 15H).

[0201] Step B: (4-((tert-butoxycarbonyl)amino)bicyclo[2,2,2]octan-1-yl)methylmethanesulfonate. Methanesulfonyl chloride (3.5 mL, 44 mmol) was added dropwise to a 0 °C solution of tert-butyl (4-(hydroxymethyl)bicyclo[2,2,2]octan-1-yl)carbamate (2 0.8 g, 11 mmol), pyridine (3.5 mL, 44 mmol) and anhydrous methylene chloride (20 mL). The mixture was stirred at room temperature for 5 hours before diluting with methylene chloride (100 ml) and quenching with H ² O (50 ml). The organic layer was separated, washed with brine (25 mL), dried over anhydrous MgSO4, filtered, concentrated to dryness under reduced pressure, and purified by flash column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 to 1:1) to provide the title compound (2.95 g, 84%) as a white solid.

Step C: tert-butyl (4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)carbamate. A solution of ( 4- (( tert -butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methylmethanesulfonate (2.95 g, 8.85 mmol) and DMSO (25 mL) was added to a sodium cyanide suspension (1.30 g, 26.5 mmol) and DMSO (5 mL). The mixture was heated at 100 °C overnight before diluting with H ² O (80 mL) and extracting with ethyl acetate (60 mL X 3). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure. The residue was triturated with MTBE (10ml) and the white solid filtered and dried under reduced pressure to give the title compound (1.7g, 73%). The filtrate was concentrated and purified by flash column chromatography (eluent: petroleum: ethyl acetate = 10:1) to give the second batch of the title compound (500 mg, 21%) as a white solid. 1H NMR (400MHz, DMSO-da) 56.39 (br s, 1H), 2.32 (s, 2H), 1.78-1.68 (m, 6H), 1.54-1.44 (m , 6H), 1.35 (s, 9H)

[0202] Step D: 2-(4-aminobicyclo[2,2,2]octan-1-yl)acetonitrile hydrochloride. A suspension of tert-butyl (4-phcyanomethyl)bicyclo[2,2,2]octan-1-yl)carbamate (2.2 g, 8.3 mmol) and ethyl acetate (10 mL) at 0 °C treated with HCl in ethyl acetate (20 mL, 80 mmol, 4.0 M). After the addition of the HCl solution, the suspension became a clear solution. The mixture was stirred at room temperature for 4 hours before being concentrated to dryness under reduced pressure. The residue was triturated with MTBE (10ml) and the solid filtered, washed with MTBE (3ml x 2) and dried under reduced pressure to give the title compound (1.55g, 93%). MS (ESI): mass calc. for C ¹⁰ H ¹⁶ N ²¹ 64.13; m/z found, 165.1 [M+H]+. 1H NMR (400 MHz, DMSO-da) 58.11 (br s, 3H), 2.40 (s, 2H), 1.78-1.67 (m, 6H), 1.62-1.51 ( m, 6H).

Synthesis and characterization of intermediate 10:

2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)ethyl acetate

[0203]

[0204] Step A: 2-(4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b/pyridin-4-yl)amino)bicyclo[2,2,2]octan -1-yl)acetonitrile. A mixture of 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.48 mmol), 2- (4-aminobicyclo[2,2,2]octan-1-yl)acetonitrile (intermediate 9, 357 mg, 1.77 mmol), N,N- diisopropylethylamine (574 mg, 4.4 mmol) and propan-2- ol (20ml). After cooling to room temperature, the suspension was isolated by filtration. The filter cake was washed with propan-2-ol (5 mL) and dried under reduced pressure to give the title compound (450 mg, 65%) as a yellow solid, which was used in the next step without further purification. . MS (ESI): mass calc. for C ²³ H ²³ N ⁵ O ⁴ S, 465.2; m/z found, 466.1 [M+H]+.

[0205] Step B: 2-(4-((5-Amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-bjpyridin-4-yl)amino)bicyclo[2,2,2]octan-1 -yl)acetonitrile. Zinc dust (279 mg, 4.29 mmol) was added to a 50 mL round bottom flask containing a mixture of 2-(4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2 ,3-b]pyridin-4-yl)amino)bicyclo[2.2.2]octan-1-yl)acetonitrile (200 mg, 0.430 mmol), sat. NH4Cl (0.6ml) and EtOH (20ml). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and diluted with ethyl acetate (20 mL). The suspension was filtered through a pad of Celite® and washed with ethyl acetate (5ml). The filtrate was concentrated to dryness under reduced pressure to give the title compound. (160 mg, 85.5%) as a brown solid, which was used in the next step without purification. MS (ESI): mass calc. for C ²³ H ²⁵ N ⁵ O ² S, 435.15; m/z found, 436.1 [M+H]+.

[0206] Step C: 2-(1 -(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d] ethyl pyrrolo[2,3-b]pyridin-2-yl)acetate. A mixture of 2-(4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b/pyridin-4-yl)amino)bicyclo[2,2,2]octan-1- yl)acetonitrile (160 mg, 0.36 mmol), ethyl 3-(ethoxyimino)propanoate hydrochloride (180 mg, 0.918 mmol) and EtOH (25 mL) were stirred at reflux for 24 hours. After cooling to room temperature, the EtOH was removed under reduced pressure and the residue was purified by preparative TLC (eluent: ethyl acetate) to give the title compound (120 mg, 61%). MS (ESI): mass calc. for C ²⁸ H ²⁹ N ⁵ O ⁴ S, 531.19; m/z found, 532.0 [M+H]+.

Synthesis and characterization of intermediate 11:

2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]sodium]pyridin- 2-yl)acetate

[0207]

[0208] Aqueous 1 N NaOH solution (2.8 mL, 2.8 mmol) was added to a solution of 2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl Ethyl )-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-bjpyridin-2-yl)acetate (intermediate 10, 500 mg, 0.941 mmol), MeOH (5 mL) and THF (5 mL).After stirring at room temperature for 24 hours, the mixture was concentrated to dryness under reduced pressure to give the title compound (600 mg) as a brown solid, which was used in the next step. no purification MS (ESI): mass calcd for C20H20N5NaO2, 385.1, m/z found, 364.0 (minus Na) [M+H]+.

Reference Example 1 Synthesis and Characterization:

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b7pyridin-2-yl)-W-^2- hydroxy-2-methylpropyl)acetamide

[0209]

[0210] Step A: 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b ]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. To ensure that the starting material is dry, 2- ( 1- (( 1r,4r)-4- (cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[ Ethyl 2,3-b7pyridin-2-yl)acetate (Intermediate 3) was heated in vacuo at 50 °C for 18 h before reaction. In a 1 L flask, 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3 Ethyl -b/pyridin-2-yl)acetate (Intermediate 3, 52.585 g, 104.01 mmol) was suspended in DMA (50 mL). 1-Amino-2-methylpropan-2-ol (50 mL) was added and the reaction was heated to 110°C for 45 minutes, then 125°C for 5 hours. The reaction was cooled to room temperature and diluted with EtOAc (800 mL). The organic layer was extracted three times with a water/brine solution where the solution consisted of 1 L of water plus 50 mL of brine. The aqueous layers were re-extracted with EtOAc (2 x 600 mL). The combined organic layers were dried over anhydrous MgSO4, concentrated to dryness, and then dried for 3 days in vacuo to provide the title compound (65.9 g, 98% yield) as a yellow foam. The product was taken to the next step without further purification. MS (ESI): mass calc. for C ²⁸ H ³² N ⁶ O ⁴ S, 548.22; m/z found, 549.2 [M+H]+.

1H NMR (400 MHz, CDCla): 58.76 (s, 1H), 8.26-8.19 (m, 2H), 7.84 (d, J = 4.1 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.50 - 7.44 (m, 2H), 6.84 (d, J = 4.2 Hz, 1H), 4.76 -4.61 (m, 1H ), 3.97 (s, 2H), 3.45 (s, 1H), 3.27 (d, J = 5.9 Hz, 2H), 2.41 (d, J = 6.5 Hz, 2H), 2.38-2.25 (m, 2H), 2.23-2.12 (m, 2H), 2.09-1.94 (m, 4H), 1.48 (qd, J = 13.6, 4.0Hz, 2H), 1.21 (s, 6H).

[0211] Step B: 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-bjpyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide. 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b7pyridin-2-yl) -W-(2-hydroxy-2-methylpropyl)acetamide (65.90 g, 102.1 mmol) was added to a 1 L flask containing a stir bar. 1,4-Dioxane (300ml) was added, followed by aqueous KOH (3M, 150ml). The reaction was heated at 80 °C for 2 h. The reaction was cooled to room temperature and the volume of solvent was reduced to approximately 200 mL on a rotary evaporator. The residue was treated with a water/brine solution (100 mL/100 mL), then extracted with 10% MeOH in CH ² Cl ² (2 x 1 L). The organic layers were combined, dried over anhydrous MgSO4, and concentrated to dryness to provide a yellow solid. The solid was suspended in CH ² Cl ² (200 mL), stirred vigorously for 30 minutes, then collected by filtration. The solid was rinsed with CH2Cl2 (100 mL), dried by blowing air through the filter, and then dried in vacuo at room temperature for 16 h to give the title compound (41.59 g, 89% yield) as a white substance. solid. MS (ESI): mass calc. for C ²² H ²⁸ N ⁶ O ² , 408.23; m/z found, 409.2 [M+H]+. 1H NMR (600 MHz, DMSO-ds): 511.85 (s, 1H), 8.50 (s, 1H), 8.21-8.10 (m, 1H), 7.49-7.43 ( m, 1H), 6.74 -6.65 (m, 1H), 4.53 - 4.42 (m, 2H), 4.07 (s, 2H), 3.08 (d, J = 6, 0 Hz, 2H), 2.58 (d, J = 6.1 Hz, 2H), 2.41 - 2.28 (m, 2H), 2.09 1.92 (m, 5H), 1.42 -1.31 (m, 2H), 1.09 (s, 6H).

Reference Example 2 Synthesis and Characterization:

2- (( 1r,4r)-4- ( 2- ( 1H -imidazol-4-yl)imidazo[4,5-a]pyrrolo[2,3-¿7pyridin-1(6H)-yl)cyclohexyl) acetonitrile

[0212]

[0213] Step A: 2- (( 1r,4r)-4- ( 2- ( 1H -imidazol-4-yl)-6-(phenylsulfonyl)imidazo[4,5-c/]pyrrolo[2,3 -b7pyridin-1 ( 6H) -yl)cyclohexyl)acetonitrile. 2-((1r,4r)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 23 0.3 g, 53.0 mmol) into a 1 L round bottom flask containing a magnetic stir bar followed by the addition of DMSO (200 mL) and methanol (200 mL). 1 H-Imidazole-4-carbaldehyde (8.56 g, 89.1 mmol) was added as a solid, followed by the addition of sodium hydrosulfite (32.7 g, 188 mmol) as a solution in water (100 mL ). The reaction vessel was fitted with a reflux condenser and heated at 90 °C on a heating block for 15 h. The reaction mixture was then cooled to room temperature and added to a flask containing water (2000 mL) with stirring, which resulted in the formation of a white precipitate. The mixture was stirred for 30 minutes and the solids collected by filtration. The solids were dried by blowing air through the filter for 6 h and then further dried in a vacuum oven heating at 60 °C for 3 days to give the title compound (22.7 g, 88% yield) as a yellow solid. MS (ESI): mass calc. for C ²⁵ H ²³ N ⁷ O ² S, 485.16; m/z found, 486.1 [M+H]+. 1H NMR (400 MHz, CDCla): 58.74 (s, 1H), 8.29 (s, 1H), 8.20 - 8.11 (m, 2H), 8.04 - 7.96 (m, 2H), 7.76 - 7.68 (m, 1H), 7.68 - 7.60 (m, 2H), 7.19 (d, J = 4.2 Hz, 1H), 5.56 (s , 1H), 2.58 (d, J = 6.3 Hz, 2H), 2.38 - 2.24 (m, 2H), 2.07 (s, 1H), 1.98 (d, J = 10.8Hz, 5H), 1.35 (q, J = 12.3Hz, 2H).

[0214] Step B: 2-((1r,4r)-4-(2-(1H-imidazol-4-yl)imidazo[4,5-a]pyrrolo[2,3-b7pyridin-1(6H)- yl)cyclohexyl)acetonitrile. The title compound was prepared using analogous conditions to those described in Example 1, Step B using 2- (( 1r,4r) -4-(2-(1H-imidazol-4-yl)-6-(phenylsulfonyl) imidazo[4,5-a]pyrrolo[2,3-b7pyridin-1(6H)-yl)cyclohexyl)acetonitrile (222 mg, 0.46 mmol) in place of 2-(1 -((1r,4r)- 4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b7pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide and the residue was purified by flash column chromatography (0-15% 2N NH3 -MeOH /EA) to give the title compound (97 mg, 69% yield). MS (ESI): mass calc. for C19H1gN/,345.17; m/z found, 346.0 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 12.61 (s, 1H), 11.86 (s, 1H), 8.55 (s, 1H), 7.92 (d, J = 1.3 Hz, 1H), 7.83 (s, 1H), 7.48 (t, J = 3.0 Hz, 1H), 6.76 (dd, J = 3.5, 1.8 Hz, 1H), 5.85 (s, 1H), 2.60 (d, J = 6.0 Hz, 2H), 2.57-2.41 (m, 2H), 2.14-1.88 (m, 5H) , 1.45-1.27 (m, 2H).

Reference Example 3 Synthesis and Characterization:

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b7pyridin-2-yl)-W-7-cyclopropylmethyl)acetamide

[0215]

[0216] Step A: 2-(1-((7r,4r,)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3 -b/pyridin-2-yl)-W-f-cyclopropylmethyl)acetamide. A mixture of 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b) was heated Ethyl ]pyridin-2-yl)acetate (intermediate 3, 555 mg, 1.06 mmol) and cyclopropylmethylamine (1.87 mL, 21.1 mmol) at 125 °C for 1 h in a microwave reactor. The residue was treated with water and then extracted with ethyl acetate. The organic layers were combined, dried over sodium sulphate, passed through a pad of silica and concentrated to dryness using a rotary evaporator to give the title compound (642mg). MS (ESI): mass calc. for C ²⁸ H ³⁰ N ⁶ O ³ S, 530.21; m/z found, 531.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD): 8.64 (s, 1H), 8.19-8.11 (m, 2H), 7.95 (d, J =4.1 Hz, 1H), 7.66 - 7.57 (m, 1H), 7.57 - 7.48 (m, 2H), 7.11 (d, J = 4.1 Hz, 1H), 4.53 (s, 1H) , 4.08 (s, 2H), 3.07 (d, J = 7.1 Hz, 2H), 2.53 (d, J = 5.9 Hz, 2H), 2.45 - 2.30 ( m, 2H), 2.14 - 2.03 (m, 5H), 1.55-1.42 (m, 2H), 1.02 - 0.94 (m, 1H), 0.54 - 0, 47 (m, 2H), 0.24-0.18 (m, 2H).

[0217] Step B: 2-(1-((7r,4r,)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-c/]pyrrolo[2,3-b/pyridin- 2-yl)-N-(cyclopropylmethyl)acetamide. To a mixture of 2-(1-((7r,4r,)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b ] Pyridin-2-yl)-N-(cyclopropylmethyl)acetamide (560 mg, 1.05 mmol) in 1,4-dioxane (4.22 mL) ^3N KOH (2.81 mL) was added. The mixture was heated at 80 °C for 1 h, then purified with basic HPLC: Xbridge Prep OBD C ¹⁸ 50 mm x 100 mm, 5 gm column (eluent 0-100% aqueous NH ⁴ OH/ACN (10 min)) ) to provide the title compound (187 mg, 46% yield). MS (ESI): mass calc. for C ²² H ²⁶ N ⁶ O, 390.22; m/z found, 391.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD): 58.57 (s, 1H), 7.50 (d, J = 3.5 Hz, 1H), 6.86 (d, J = 3.5 Hz, 1H ), 4.57 (s, 1H), 4.11 (s, 2H), 3.13 (d, J = 7.0 Hz, 2H), 2.67 - 2.52 (m, 4H), 2 0.20 - 2.03 (m, 5H), 1.58-1.44 (m, 2H), 1.12 - 0.97 (m, 1H), 0.60 - 0.48 (m, 2H) , 0.31 -0.22 (m, 2H).

Reference Example 4 Synthesis and Characterization:

N-(2-cyanoethyl)-2-(1-((ir,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-bjpyridin- 2-yl)acetamide

[0218]

[0219] To a solution of sodium 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4 PyBOP (870 mg, 1.67 mmol) and DIPEA (0. 60 mL, 3.5 mmol).The reaction mixture was stirred at room temperature for 40 h.After removing the DMF in vacuo, the residue was purified by flash column chromatography using 50-100% ethyl acetate in heptane. The collected fractions were concentrated in vacuo to a small volume and the white solid that had precipitated was filtered, washed with 10% MeOH in CH ² Cl ² and dried to provide the title compound (75 mg, 17% of The filtrate was concentrated to dryness and purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 mm X 30 mm column (eluent 10 - 90% CH ³ CN in water, 0.1% TFA) to to provide a clear oil This material was dissolved in 10% MeOH in CH ² CL, passed through three 500 mg columns of SILICYCLE SPE-R66030B-03P carbonate (cartridge ho solid phase extraction with SiliaBond acid scavenger) to remove TFA and eluted with 10% MeOH in CH ² Cl ² to give an additional fraction of the title compound (88 mg, 20% yield). The two fractions were combined to provide the final product (163 mg, 37% yield) as a white solid. MS (ESI): mass calc. for C ²¹ H ²³ N ⁷ O, 389.20; m/z found, 390.3 [M+H]+. 1H NMR (400 MHz, CD ³ OD): 58.53 (s, 1H), 7.48 (d, J = 3.0 Hz, 1H), 6.84 (d, J = 3.5 Hz, 1H ), 4.51 (br s, 1H), 4.12 (s, 2H), 3.50 (t, J = 6.6 Hz, 2H), 2.71 (t, J = 6.6 Hz, 2H), 2.45-2.63 (m, 4H), 2.03-2.19 (m, 5H), 1.44-1.57 (m, 2H).

Reference Example 5 Synthesis and Characterization:

2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b/pyridin-2-yl)-W-(ietrahydro-2H -pyran-4-yl)acetamide

[0220]

[0221] A mixture of ethyl 2-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)acetate (intermediate 3, 309 mg, 0.61 mmol) and 4-aminotetrahydropyran (195 mg, 1.93 mmol) in 1,4-dioxane (0.5 mL) was heated in a microwave reactor at 180 °C for 1 h, then the reaction mixture was diluted with 1,4-dioxane (1.5 mL), treated with aqueous 3N KOH (2 mL) and heated to 80 °C for 1.5 hours The residue was then treated with water (10ml) and extracted with CH ² Cl ² (3 x 50ml) The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (5-10% MeOH/CH ² Cl ² ) to give the title compound (146 mg, 57% yield) MS (ESI): mass calcd for C ²³ H ²⁸ N ⁶ O ² , 420.23, m/z found, 421.2 [M+H]+, 1H NMR (600 MHz, DMSO-da): 511.84 (s, 1H), 8.49 ( s, 1H), 8.36 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 3.0 Hz, 1H)), 6, 73 -6.67 (m, 1H), 4.54 -4.41 (m, 1H), 3.98 (s, 2H), 3.86 - 3.81 (m, 2H), 3.81 - 3.74 (m, 1H), 3.40 - 3.34 (m, 2H), 2.60 (d, J = 6.0 Hz, 2H), 2.41 - 2.29 (m, 2H) , 2.10 - 2.01 (m, 1H), 2.00-1.93 (m, 4H), 1.77-1.70 (m, 2H), 1.49-1.33 (m, 4H).

Reference Example 6 Synthesis and Characterization:

2-((7r;4r,M-(2-(2-Oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b/ pyridin-1(6Hj-yl)cyclohexyl)acetonitrile

[0222]

[0223] A solution of sodium 2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b/pyridin-2-yl) acetate (Intermediate 4, 200 mg, 0.557 mmol), 4-(trifluoromethyl)piperidine (85.0 mg, 0.557 mmol), DlPEA (144 mg, 1.11 mmol) and DMF (5 mL) were stirred at 0 °C for 1 h. PyBrOP (311 mg, 0.668 mmol) was then added and stirred at room temperature overnight. The mixture was quenched with 10 mL of water and purified by preparative HPLC using a Boston Green ODS 150 column. mm x 30 mm, 5 gm (eluent: water (0.05%) HCl-18 to 48% ACN, v/v) to give the title compound (81 mg, 30% yield) as a solid light brown MS (ESI): mass calcd for C ²⁴ H ²⁷ F ³ N ⁶ O, 472.2, m/z found, 473.2 [M+H]+ 1H NMR (400 MHz, DMSO-ds ): 512.69 (s, 1H), 8.88 (s, 1H), 7.79 - 7.76 (m, 1H), 6.99 -6.96 (m, 1H), 4.77 - 4.63 (m, 2H), 4.50 -4.43 (m, 1H), 4.17 -4.10 (m, 1H), 3.29 - 3.20 (m, 1H), 2, 77 - 2.66 (m, 2H), 2.58 (d, J = 6.0 Hz, 2H),2, 53-2.47 (m, 4H) 2.13-1.85 (m, 6H), 1.66-1.53 (m, 1H), 1.45-1.22 (m, 3H).

Reference Example 7 Synthesis and Characterization:

2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b/pyridin-2-yl)-W-í4-(hydroxymethyl )phenyl)acetamide

[0224]

[0225] A solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d|pyrrolo[2,3-b]pyridin-2 -yl)acetate (intermediate 4, 300 mg, 0.835 mmol), (4-aminophenyl)methanol hydrochloride (133 mg, 0.835 mmol), DIPEA (216 mg, 1.67 mmol) and DMF (5 mL) were stirred at 0 °C for 1 hour. PyBrOP (467 mg, 1.00 mmol) was added and stirred at room temperature overnight. The mixture was quenched with 10 mL of water and purified by C ¹⁸ preparative HPLC using a Waters Xbridge Prep OBD C ¹⁸ 150 mm x 30 mm, 5 gm column (eluent: water (0.05% v/v ammonia hydroxide). v) -MeOH 44 to 55%, v/v) to give the title compound (43 mg, 11% yield) as a white solid. MS (ESI): mass calc. for C25H26N6O2,442.2; m/z found, 443.2 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 511.86 (br s, 1H), 10.40 (s, 1H), 8.52 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.49 - 7.45 (m, 1H), 7.26 (d, J = 8.0 Hz, 2H), 6.75 -6.71 (m, 1H), 5.15 - 5.08 (m, 1H), 4.65 -4.54 (m, 1H), 4.46 -4.41 (m, 2H), 4.24 (s, 2H), 2.58 (d , J = 6.0 Hz, 2H), 2.45-2.30 (m, 2H), 2.11-1.93 (m, 5H), 1.48-1.33 (m, 2H).

Reference Example 8 Synthesis and Characterization:

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b7pyridin-2-yl)-W-f4-( cyanomethyl)phenyl)acetamide

[0226]

[0227] A mixture of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- Sodium yl)acetate (intermediate 4, 200 mg, 0.557 mmol), 2-(4-aminophenyl)acetonitrile hydrochloride (93.8 mg, 0.557 mmol), DIPEA (144 mg, 1.11 mmol) and DMF (5 ml) were stirred at 0 °C for 1 h. PyBrOP (311 mg, 0.668 mmol) was added and stirred at room temperature overnight. The mixture was quenched with 10 mL of water and purified by preparative HPLC using a 150 mm x 25 mm, 10 gm Kromasil column (eluent: water (0.05% v/v ammonia hydroxide)-27% ACN 37%, v/v) and then by preparative TLC (CH ² CL:MeOH = 10:1) to give the title compound (12 mg, 4% yield) as a white solid. MS (ESI): mass calc. for C ²⁶ H ²⁵ N ⁷ O, 451.2; m/z found, 452.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD): 58.55 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 3.6 Hz, 1H ), 7.33 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 3.6 Hz, 1H), 4.68 - 4.54 (m, 2H), 4.31 - 4.25 (m, 1H), 3.86 (s, 2H), 2.67 - 2.49 (m, 4H), 2.20 - 2.05 (m, 5H), 1.55-1 .41 (m, 2H).

Reference Example 9 Synthesis and Characterization:

2- (( 1r,4r)-4- ( 2- ( 1H -1,2,4-Triazol-3-yl)imidazo[4,5-d|pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile

[0228]

[0229] Step A: 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-( 1H- 1,2,4-triazol-3-yl)imidazo[4,5-d| pyrrolo[2,3-b/pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b/pyridin-4-yl )amino)cyclohexyl)acetonitrile (Intermediate 1, 152 mg, 0.346 mmol) and 1H -pyrazole-3-carbaldehyde (74 mg, 0.762 mmol) as solids. DMSO (1.7ml), MeOH (1.7ml) and distilled water (0.9ml) were added resulting in a yellow mixture. Sodium hydrosulfite (183 mg, 1.05 mmol) was added as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100 °C and heated for 3 h. The reaction mixture was then cooled to room temperature and added to a flask containing 50 mL of water with stirring, which resulted in the formation of a white precipitate. The mixture was stirred for 30 minutes and the solids collected by filtration. The solids retained a large amount of water, so they were initially dried by blowing air through the filter for 6 h and then further dried in a vacuum oven heating to 60 °C to give the title compound (154 mg, 91 % yield). which was used in the next reaction without further purification. MS (ESI): mass calc. for C ²⁴ H ²² N ⁸ O ² S, 486.16; m/z found, 487.2 [M+H]+.

[0230] Step B: 2-((1r,4r)-4-(2-(1H-1,2,4-Triazol-3-yl)imidazo[4,5-d|pyrrolo[2,3-b /pyridin-1(6H)-yl)cyclohexyl)acetonitrile. To a 10 mL microwave vial was added 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-(1H-1,2,4-triazol-3-yl)imidazo[4, 5-a]pyrrolo[2,3-b/pyridin-1(6H)-yl)cyclohexyl)acetonitrile (154 mg, 0.317 mmol) as a solid, followed by addition of dioxane (2 mL) and KOH (aq.) (1.5ml, 3M, 4.5mmol). The vial was sealed and heated to 80°C using a heating block for 1 hour. The reaction was cooled to room temperature and purified by basic HPLC using a Waters Xbridge C ¹⁸ OBD 50 mm x 100 mm, 5 gm column (eluent 0-100% aqueous NH ⁴ OH/ACN (10 min) to give the compound of title (18 mg, 16% yield) MS (ESI): mass calculated for C ¹⁸ H ¹⁸ N ⁸ , 346.17 m/z found, 347.2 [M+H]+, 1H NMR (500 MHz, DMSO-afe): 12.04 (s, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 7.54 (t, J = 3.0 Hz, 1H), 6 .88 -6.74 (m, 1H), 5.68 (s, 1H), 2.60 (d, J = 6.1 Hz, 2H), 2.49 - 2.41 (m, 2H), 2.13-1.91 (m, 6H), 1.43-1.29 (m, 2H).

Reference Example 10 Synthesis and Characterization:

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-bjpyridin-2-yl)-W-^( tetrahydro-2H-pyran-4-yl)methyl)acetamide

[0231]

[0232] To a microwave vial was added 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d|pyrrolo [2,3-b/pyridin-2-yl)acetate (intermediate 3, 300 mg, 0.593 mmol) and 4-aminomethyltetrahydropyran (683 mg, 5.93 mmol). The resulting solution was stirred at 125 °C for 1 hour. Dioxane (2.37 mL) and KOH (3M in water, 1.58 mL, 4.75 mmol) were then added and the reaction was stirred in the microwave at 80 °C for 1 h. The reaction was purified by basic HPLC using a Waters Xbridge Prep OBD C18150 mm X 30 mm, 5 gm column (eluent 0-100% water (0.5% NH4OH)/ACN (10 min)) to give the title compound (97 mg, 38% yield). MS (ESI): mass calc. for C ²⁴ H ³⁰ N ⁶ O ² , 434.24; m/z found, 435.2 [M+H]+. 1H NMR (500 MHz, CD ³ OD): 58.43 (s, 1H), 7.38 (d, J = 3.5 Hz, 1H), 6.74 (d, J = 3.5 Hz, 1H ), 4.43 (s, 1H), 4.03 - 3.96 (m, 2H), 3.89 - 3.79 (m, 2H), 3.34 - 3.25 (m, 2H), 3.04 (d, J = 6.8 Hz, 71 2H), 2.54-2.38 (m, 4H), 2.08-1.96 (m, 5H), 1.74-1.63 (m, 1H), 1.59-1.54 (m, 2H), 1.46-1.33 (m, 2H), 1.25-1.14 (m, 2H).

Reference Example 11 Synthesis and Characterization:

2-((1r,4r)-4-(2-(Oxazol-4-yl)imidazo[4,5-d|pyrrolo[2,3-b/pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0233]

[0234] Step A: 2-((7r,4r7-4-(2-(Oxazol-4-yl)-6-(phenylsulfonyl)imidazo[4,5-a(|pyrrolo[2,3-b7pyridin-1 ( ^6Hj -¡l)cyclohex¡l)aceton¡trile To a 20 mL microwave vial was added 2-((ir,4r1-4-((5-nitro-1-(phenylsulfonyl)- 1H-pyrrolo[2,3-bjpyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 190 mg, 0.432 mmol) and oxazole-4-carbaldehyde (94 mg, 0.968 mmol) were added as solids DMSO (2 mL), MeOH (2 mL) and distilled water (0.9 mL) resulting in a yellow mixture Sodium hydrosulfite (184 mg, 1.06 mmol) was then added as a solid and the vial sealed. The vial was placed on a heating block preheated to 100 C. The progress of the reaction was followed by NMR and when all Intermediate 1 had been consumed, the reaction mixture was cooled to room temperature and added to a flask containing 50 mL of water with stirring, which resulted in the formation of a white precipitate The mixture was stirred for 30 minutes and the solids collected by filtration. The solids retained a large amount of water, so they were initially dried by blowing air through the filter for ⁶ h and then further dried in a vacuum oven heating to 60 °C to give the title compound (178 mg, 84 % Yield) as a tan amorphous solid, which was used in the next step without further purification. MS (ESI): mass calc. for C ²⁵ H ²² N ⁶ O ³ S, 486.15; m/z found, 486.9 [M+H]+.

[0235] Step B: 2-((7r,4r7-4-(2-(Oxazol-4-yl)imidazo[4,5-c/|pyrrolo[2,3-b7pyridin-1(6H)-yl) cyclohexyl)acetonitrile The title compound was prepared using analogous conditions to those described in Example 1, Step B using 2-((1r,4r)-4-(2-(Oxazol-4-yl)-6-(phenylsulfonyl )imidazo[4,5-a(|pyrrolo[2,3-bjpyridin-1(6H)-yl)cyclohexyl)acetonitrile (178 mg, 0.37 mmol) in place of 2-(1-((1r,4r )-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1 ^,6- dihydroimidazo[4,5-c/|pyrrolo[2,3-b7pyridin-2-yl)-W-(2-hydroxy-2- methylpropyl)acetamide and purified by basic HPLC: using a Waters Xbridge Prep OBD C ¹⁸ 50 mm x 100 mm, 5 gm column (eluent 0-100% aqueous NH ⁴ OH/ACN (10 min)) to provide the title compound (38 mg, 30% yield) Ms (ESI): mass calcd for C ¹⁹ H ¹⁸ N ⁶ O, 346.15, m/z found, 346.9 [M+H]+ 1H NMR (500 MHz, DMSO-d6): 11.99 (s, 1H), 8.83 (d, J = 1.1 Hz, 1H), 8.70 (d, J = 1.0 Hz, 1H), 8 .62 (s, 1H), 7.52 (d, J = 3.4 Hz, 1H), 6.79 (d, J = 3.5 Hz, 1H), 5.33 - 5.17 (m, 1H), 2.58 (d, J = 6.1 Hz, 2H), 2.50-2.40 (m, 2H), 2.11-1.91 (m, 5H), 1, 35 (tt, J =13.7, 7.2Hz, ^2H ).

Reference Example 12 Synthesis and Characterization:

2-((1r,4r)-4-(2-(2-(4-Hydroxypiperidin-1-yl)-2-oxoethyl)imidazo[4,5-a(|pyrrolo[2,3-bjpyridin-1 ( ^6H )-yl)cyclohexyl)acetonitrile

[0236]

[0237] A mixture of sodium 2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b7pyridin-2- il)acetate (intermediate 4, 200 mg, 0.557 mmol), piperidin-4-ol ^{( 56} mg, 0.557 mmol), DIPEA (144 mg, 1.11 mmol) and DMF (5 mL) were stirred at 0 °C for 1 h PyBrOP (311 mg, 0.668 mmol) was added and the reaction mixture was stirred overnight at room temperature The reaction mixture was quenched with 10 mL of water, extracted with CH ² Cl ² (2 x 10 mL) and concentrated under reduced pressure.The resulting residue was purified by acidic preparative HPLC (Gemini 150x25 5 gm (eluent: water (0.05%) HCl-0-33% ACN, v/v) and then by basic preparative HPLC using a Kromasil 150 mm X 25 mm column, 10 gm (eluent: water (0.05% ammonium hydroxide v/v)-5% to 35% ACN, v/v) to give the compound of the titer (21 mg, 9% yield) as a white solid MS (ESI): mass calculated for C ²³ H ²⁸ N ⁶ O ² , 420.23 m/z found, 421.2 [M+H]+ 1 H NMR (400 MHz, DMSO-afe): 11.85 (br s, 1H), 8.50 (s, 1H), 7.49-7.43 (m, 1H), 6.70 (br s , 1H), 4.76 (d, J = 4.0 Hz, 1H), 4.44 -4.32 (m, 1H), 4.25 (s, 2H), 3.95 - 3.83 ( m, 2H), 3.76 -3.66 (m, 1H), 3.11 - 3.02 (m, 1H), 2.58 (d, J = 6.0 Hz, 3H), 2.41 - 2.26 (m, 2H), 2.09-1.89 (m, 5H), 1.79-1.65 (m, 2H), 1.42 1.18 (m, 4H)

Example 13 Synthesis and characterization:

2-Cyano- n-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b/pyridin-2-yl )methyl)ethanesulfonamide

[0238]

[0239] 2-Cyanoethanesulfonyl chloride (133 mg, 0.435 mmol, purity 50%) dropwise to a solution of 2- (( 1r,4r)-4- ( 2- (aminomethyl)imidazo[4,5-d ]pyrrolo[2,3-b/pyridin-1(6H)-yl)cyclohexyl)acetonitrile (Intermediate 5, 150 mg, 0.435 mmol), triethylamine (0.30 mL, 2.2 mmol) and CH ² CL (5 ml) and stirred for 30 minutes at 15 °C. The reaction mixture was diluted with CH2Cl2 (10 mL), washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC using an Agela DuraShell 150 mm x 25 mm, 5 gm column (eluent: 16% to 46% (v/v) CH ³ CN and H ² O with 10 mM NH ⁴ HCO ³ ) to provide the title compound (30 mg, 16% yield) as a white solid. MS (ESI): mass calc. for C ²⁰ H ²³ N ⁷ O ² S, 425.16; m/z found, 426.2 [M+H]+. 1H NMR (400MHz, CDCh): 59.76 (s, 1H), 8.69 (s, 1H), 8.01 (br s, 1H), 7.37-7.29 (m, 1H), 6 .59 (s, 1H), 4.73 (s, 2H), 4.51 -4.36 (m, 1H), 3.47 (t, J = 7.6 Hz, 2H), 3.07 ( t, J = 7.6 Hz, 2H), 2.41 (d, J = 6.4 Hz, 2H), 2.36 - 2.20 (m, 2H), 2.20 - 2.09 (m , 2H), 2.06-1.96 (m, 1H), 1.89-1.73 (m, 2H), 1.52-1.38 (m, 2H).

Example 14 Synthesis and characterization:

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b/pyridin-2-yl)-W-( 'pyrimidin-4-ylmethyl)acetamide

[0240]

[0241] To a 10 mL microwave vial was added 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2, Sodium 3-bjpyridin-2-yl)acetate (intermediate 4, 151 mg, 0.420 mmol) as a solid followed by DMF (1.7 mL). PyBOP (329 mg, 0.632 mmol) was added in one portion and immediately formed a canary yellow color. The reaction was stirred for 15 minutes before the addition of DIPEA (0.29 mL, 1.7 mmol), followed by 2-aminomethylpyrazine hydrochloride (120 mg, 0.824 mmol). Upon completion, the reaction was diluted with MeOH (4 mL) and purified by basic HPLC: using a Waters Xbridge column 50 mm x 100 mm, 5 gm (eluent 0-100% aqueous NH ⁴ OH/ACN (10 min ))) to provide the title compound (12 mg, 7% yield). MS (ESI): mass calc. for C ²³ H ²⁴ N ⁸ O, 428.21; m/z found, 429.0 [M+H]+. 1H NMR (500 MHz, CDCh): 510.79 (s, 1H), 9.10 (d, J = 1.4 Hz, 1H), 8.72 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 7.45 (dd, J = 3.5, 2.5 Hz, 1H), 7.29 - 7.26 (m, 1H), 6.72 (dd, J = 3.7, 1.8 Hz, 1H), 4.71 - 4.47 (m, 3H), 4.13 (s, 2H), 2.70 - 2.47 (m, 2H), 2.42 (d, J = 6.5 Hz, 2H), 2.18 (d, J = 13.3 Hz, 2H), 2.14-1.97 (m, 3H), 1.93-1.70 ( m, 2H), 1.58-1.37 (m, 3H).

Example 15 Synthesis and characterization:

2 -(1 -( (1 r ,4 r ) -4 -(C ianomethyl) c ic lo hex yl) -1 ,6 -d ih idro imidazo [4 ,5 -d ]p ir ro lo [2 ,3 -b /p ir id in -2 - il) -W -(3 -h id ro x i-2 ,2 -d im eti lp ro p il)ace ta m ida

[0242]

[0243] A mixture of 2-(1-((ir,4r1-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-bjpyridin-2-yl)acetate sodium (Intermediate 4, 300 mg, 0.835 mmol), 3-amino-2,2-dimethylpropan-1-ol (86 mg, 0.84 mmol), DiPEA (216 mg, 1.67 mmol), and DMF (5 mL) was stirred at 0 °C for 1 h. PyBrOP (467 mg, 1.00 mmol) was added and the reaction stirred overnight at room temperature. The mixture was quenched with 10 mL of water and concentrated under pressure. reduced to dryness The residue was purified by preparative basic HPLC using a 150 mm x 25 mm 10 pm Kromasil column (eluent: water (0.05% v/v ammonium hydroxide)-20 to 30% ACN, v /v) twice to give the title compound (35 mg, 10% yield) as a white solid MS (ESI): mass calcd for C ²³ H ³⁰ N ⁶ O ² , 422.24, m/z found , 423.2 [M+H]+.1H NMR (400 MHz, CD ³ OD): 58.53 (s, 1H), 7.48 (d, J = 3.6 Hz, 1H), 6.84 (d, J = 3.2 Hz, 1H), 4.65 -4.47 (m, 1H), 4.16 - 4.08 (m, 2H), 3.25 (s, 2H), 3, 1 5 (s, 2H), 2.69 - 2.48 (m, 4H), 2.21 - 2.00 (m, 5H), 1.58-1.42 (m, 2H), 0.98 - 0.85 (m, 6H).

Reference Example 16 Synthesis and Characterization:

2- (( 1r,4r)-4- ( 2- ( 2H -1,2,3-Triazol-4-yl)imidazo[4,5-d|pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile

[0244]

[0245] Step A: 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-(2H-1,2,3-triazol-4-yl)imidazo[4,5-d|pyrrolo [2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile. To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino)cyclohexyl)acetonitrile (Intermediate 1, 135 mg, 0.307 mmol) and 1 H-[1,2,3]triazole-4-carbaldehyde (59 mg, 0.61 mmol) as solids. DMSO (1.5ml), MeOH (1.5ml) and distilled water (0.8ml) were added resulting in a yellow mixture. Sodium hydrosulfite (134 mg, 0.768 mmol) was added as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100 °C and heated for 3 h. The reaction mixture was cooled to room temperature and added to a flask containing 50 mL of water with stirring, which resulted in the formation of a white precipitate. The mixture was stirred for 30 minutes and the solids collected by filtration. The solids retained a large amount of water, so they were initially dried by blowing air through the filter for 6 h and then further dried in a vacuum oven heating to 60 °C to give the title compound (122 mg, 81 % yield). which was used in the next reaction without further purification. MS (ESI): mass calc. for C ²⁴ H ²² N ⁸ O ² S, 486.16; m/z found, 487.2 [M+H]+. 1H NMR (500 MHz, DMSO-ds): 58.79 (s, 1H), 8.20-8.11 (m, 2H), 8.02 (d, J =4.1 Hz, 1H), 7 .76 - 7.68 (m, 1H), 7.67 - 7.60 (m, 2H), 7.22 (d, J = 4.2 Hz, 1H), 5.44 (s, 1H), 3.68 - 3.39 (m, 2H), 2.59 (d, J = 6.4 Hz, 2H), 2.54 (s, 1H), 2.32 (q, J = 12.6 Hz , 2H), 2.15-1.90 (m, 4H), 1.35 (q, J = 12.2 Hz, 2H).

[0246] Step B: 2-((1r,4r)-4-(2-(2H-1,2,3-Triazol-4-yl)imidazo[4,5-a]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile. The title compound was prepared using analogous conditions to those described in Example 1, Step B using 2- (( 1r,4r) -4-(6-(phenylsulfonyl)-2-(2H-1,2,3-triazole -4-yl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (122 mg, 0.25 mmol) in place of 2-(1- ((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-W- (2-hydroxy-2-methylpropyl)acetamide to provide the title compound (32 mg, 35% yield). MS (ESI): mass calc. for C ¹⁸ H ¹⁸ N ⁸ , 346.17; m/z found, 347.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 511.96 (s, 1h), 8.62 (s, 1H), 8.44 (s, 1H), 7.59-7.45 (m, 1H), 6.85 - 6.73 (m, 1H), 5.82 - 5.34 (m, 1H), 2.60 (d, J = 6.1 Hz, 2H), 2.54 (s, 1H) , 2.02 (q, J = 16.1 Hz, 5H), 1.46-1.31 (m, 2H), 1.04 (d, J = 6.1 Hz, 2H).

Reference Examples 17A and B:

Example 17A Synthesis and characterization:

(É)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N-hydroxybenzimidamide and

Example 17B Synthesis and characterization:

(Z)-N-((1-((1 r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)methyl)-N'-hydroxybenzimidamide

[0247]

[0248] A solution of 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile (intermediate 5, 250 mg, 0.725 mmol), N-hydroxybenzimidoyl chloride (113 mg, 0.725 mmol), triethylamine (0.51 mL, 3.6 mmol), and DMF (5 mL) were stirred for 2 h at 15° c. Water (20ml) was added and a brown precipitate formed which was isolated by filtration, washed with water (3ml x 2) and dried under high vacuum to give a brown solid (190mg). A portion of the (E)/(Z) mixture was reserved for later use as a mixture and a portion (130 mg) of the E)/(Z) mixture was subjected to preparative HPLC using a Phenomenex Gemini 150 mm X 25 mm, 10 pm column (eluent: 13% to 43% (v/v) CH ³ CN and aqueous HCl (0.006 N) to purify and separate the (E) and (Z) isomers. Fractions of each isomer were collected and treated with saturated aqueous NaHC03 until pH = 7-8.Volatile organics were removed under reduced pressure and the precipitate isolated by filtration and washed with water (2 mL X 3).The filter cake was slurried in water (10 ml) and CH ³ CN (2 ml), the mixture was frozen using dry ice/acetone and then lyophilized to dryness to give (£)-N-((1-((1r,4r)-4-(cyanomethyl) cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)-N'-hydroxybenzimidamide as the trans-(E) conformation (5 mg, 2% yield) as an off-white solid MS (ESI): mass calculated for C ²⁴ H ²⁵ N ⁷ O, 427.21; d , 428.1 [ ^m +H]+. 1H NMR (400 MHz, DMSO-afe): 11.89 (s, 1H), 8.91 (s, 1H), 8.55 (s, 1H), 7.48 (d, J = 3.2 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.27 - 7.20 (m, 2H), 6.97 -6.87 (m, 2H), 6.73 (d, J = 3.2 Hz, 1H), 4.72 (d, J = 5.2 Hz, 2H), 4.67 - 4.53 (m, 1H), 2.58 (d, J = 6.0 Hz, 2H), 2.43-2.28 (m, 2H), 2.08-1.89 (m, 5H), 1.54-1.37 (m, 2H). The following compound was also isolated: (Z)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)methyl)-N'-hydroxybenzimidamide as cis-(Z) isomer (7 mg, 2% yield). MS (ESI): mass calc. for C ²⁴ H ²⁵ N ⁷ O, 427.21; m/z found, 428.0 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 11.87 (s, 1H), 9.93 (br. s., 1H), 8.52 (s, 1H), 7.52-7.44 ( m, 3H), 7.44-7.35 (m, 3H), 6.69 (d, J = 2.8 Hz, 1H), 6.41 (t, J = 5.6 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 4.40 -4.20 (m, 1H), 2.58 (d, J = 5.2 Hz, 2H), 2.37 - 2 .16 (m, 2H), 2.04-1.83 (m, 5H), 1.46-1.32 (m, 2H).

Reference Example 18 Synthesis and Characterization:

2-((1r,4r)-4-(2-(2-(3-Hydroxyazetidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile

[0249]

[0250] To a solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)acetate (intermediate 4, 300 mg, 0.835 mmol), azetidin-3-ol (67 mg, 0.92 mmol), DIPEA (0.290 mL, 1.67 mmol) and DMF (5 mL) were added PyBrOP (428 mg, 0.918 mmol) at 0 °C and stirred at room temperature for 3.5 h. The mixture was quenched with 10 ml of water and extracted with EtOAc (3 x 20 ml). Both the organic and aqueous phases were concentrated and purified by preparative HPLC using an Xtimate C ¹⁸ 150 X 25 mm X 5 pm column (eluent: 12% to 32% (v/v) CH ³ CN and H ² O with 10 mM NH ⁴ HCO ³ ) to provide the title compound (62 mg, 18% yield) as a solid yellow. MS (ESI): mass calc. for C ²¹ H ²⁴ N ⁶ O ² , 392.20; m/z found, 393.1 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 11.84 (br s, 1H), 8.50 (s, 1H), 7.47 (br s, 1H), 6.74-6.68 (m , 1H), 5.80 (br s, 1H), 4.53 - 4.37 (m, 3H), 4.16 - 3.94 (m, 4H), 3.66 - 3.59 (m, 1H), 2.64 - 2.55 (m, 2H), 2.42 - 2.26 (m, 2H), 2.10-1.83 (m, 5H), 1.47-1.35 ( m, 2H).

Example 19 Synthesis and characterization:

N-((7r,4r,)-4-(Cyanomethyl)cyclohexyl)-2-(1-((7r;4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a ]pyrrolo[2,3-b/pyridin-2-yl)acetamide

[0251]

[0252] A solution of sodium 2-(1-((ir,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-bjpyridin-2-yl )acetate (Intermediate 4, 300 mg, 0.835 mmol), 2-((7r,4r,)-4-aminocyclohexyl)acetonitrile (145 mg, 0.835 mmol), DIPEA (324 mg, 2.50 mmol), DMF (10 mL) and PyBrOP (467 mg, 1.00 mmol) was stirred at room temperature for 3 h. The reaction was quenched with 5 mL of water and concentrated to dryness. The residue was purified by preparative basic HPLC using a 150 mm x 25 mm, 10 gm Kromasil column (eluent: 14% to 44% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (35 mg, 9% yield) as a white solid. MS (ESI): mass calc. for C ²⁶ H ³¹ N ⁷ O, 457.26; m/z found, 458.2 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 511.83 (br s, 1H), 8.49 (s, 1H), 8.29 -8.20 (m, 1H), 7.49 - 7.43 (m, 1H), 6.75 - 6.66 (m, 1H), 4.56 - 4.10 (m, 2H), 3.95 (s, 2H), 2.63 - 2.56 (m , 2H), 2.45 - 2.40 (m, 2H), 2.37 - 2.27 (m, 2H), 2.07-1.92 (m, 4H), 1.90-1.72 (m, 4H), 1.67-1.52 (m, 2H), 1.46-1.31 (m, 2H), 1.31-1.17 (m, 2H), 1.17-1 .03 (m, 2H)).

Reference Example 20 Synthesis and Characterization:

2-(1-((7r,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-W- phenylacetamide.

[0253]

[0254] To a solution of sodium 2-(1-((fr,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d|pyrrolo[2,3-bjpyridin-2 -yl)acetate (intermediate 4, 50 mg, 0.14 mmol) and aniline (48 mg, 0.52 mmol) in DMF (2 mL) were added HATU (180 mg, 0.47 mmol) and DIPEA (0. 12 mL, 0.70 mmol) mmol) and stirred at room temperature for 18 h. The reaction was concentrated to dryness, water was added and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated to dryness, and purified by reverse phase HPLC using a Phenomenex Luna C ¹⁸ 100 mm X 30 mm, 5 gm column (5-95% mobile phase gradient). ACN in H ² O (both with 0.1% TFA), v/v) to give the title compound (27 mg, 37% yield). MS (ESI): mass calc. for C ²⁴ H ²⁴ N ⁶ O, 412.20; m/z found, 413.3 [M+H]+. 1H NMR (400 MHz, CDCh): 59.64 (br s, 1H), 8.79 (s, 1H), 7.55 (d, J =7.72 Hz, 2H), 7.43 (t, J =3.03 Hz, 1H), 7.32 (t, J =7.67 Hz, 2H), 7.12 (t, J =7.50 Hz, 1H), 6.74 (dd, J = 2.02, 3.54 Hz, 1H), 4.54 (br s, 1H), 4.13-4.17 (m, 2H), 2.55 (br s, 1H), 2.44 (d , J =6.57 Hz, 2H), 2.21 (br d, J =13.14 Hz, 2H), 2.01-2.13 (m, 3H), 1.45-1.58 (m , 3H).

Example 21 Synthesis and characterization:

2-(1-((1r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b/pyridin-2-yl)-A/-('( ( 1S,3R,5R,7S)-3-hydroxyadamantan-1-yl]methyl)acetamide

[0255]

[0256] A solution of sodium 2-(1-((ir,4r1-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-bjpyridin-2-yl )acetate (Intermediate 4, 300 mg, 0.835 mmol), ( 1S, 3R, 5R, 7S)-3-(aminomethyl)adamantan-1-ol hydrochloride (182 mg, 0.835 mmol), DIPEA (216 mg, 1.67 mmol) and DMF (5 mL) were stirred at 0 °C for 1 h. PyBrOP (467 mg, 1.00 mmol) was then added and stirred at room temperature overnight. The mixture was quenched with 10 mL of water and purified by preparative basic HPLC using a 150 mm x 25 mm, 5 gm DuraShell column (eluent: water (0.05% v/v ammonium hydroxide)-16 to 46% ACN, v/v ) and by preparative TLC (CH ² CL:MeOH = 10:1) to give the title compound (64 mg, 15% yield) as a white solid MS (ESI): mass calcd for C ²⁹ H ³⁶ N ⁶ O ² , 500.29, m/z found, 501.2 [M+H]+, 1H NMR (400 MHz, DMSO-afe): 511.84 (br s, 1H), 8.49 (s, 1H), 8.20 - 8.14 (m, 1H), 7.47 -7.44 (m, 1H), 6.72 -6.69 (m, 1H), 4.52 -4.41 (br s, 1H), 4.39 (s, 1H), 4.03 (s, 2H), 2.87 (d, J = 6.4 Hz, 2H), 2.57 (d, J = 6 0 Hz, 2H), 2.41-2.27 (m, 2H), 2.11-1.93 (m, 7H), 1.56-1.44 (m, 6H), 1.41- 1.29 (m, 8H).

Example 22 Synthesis and characterization:

W-('2-Cyano-2-methylpropyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -bjpyridin-2-yl)acetamide

[0257]

[0258] A solution of sodium 2-(1-((1r,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-bjpyridin-2 -yl)acetate (intermediate 4, 300 mg, 0.835 mmol), 3-amino-2,2-dimethylpropanenitrile (82.0 mg, 0.835 mmol), DIPEA (216 mg, 1.67 mmol), and DMF (5 mL) were stirred at 0 °C for 1 h. PyBrOP (467 mg, 1.00 mmol) was then added and the reaction mixture stirred overnight at room temperature. The mixture was quenched with 10 mL of water and quenched. purified by preparative HPLC using a Waters Xbridge Prep OBD C18150 mm X 30 mm 5 gm column (eluent: 28% water (0.05% v/v ammonia hydroxide)-ACN to give the title compound (58 mg, 16% yield) as a white solid MS (ESI): mass calculated for C ²³ H ²⁷ N ⁷ O, 417.23 m/z found, 418.2 [M+H]+ 1H NMR (400 MHz, DMSO- sjd: 511.86 (br s, 1H), 8.71 - 8.66 (m, 1H), 8.50 (s, 1H), 7.48 - 7.45 (m, 1H), 6.73 -6.69 (m, 1H), 4.53 -4.42 (m, 1H), 4.10 (s, 2H), 3.33 - 3.31 (m, 1H), 2.57 (d , J = 5.6 Hz, 2H), 2.41-2.27 (m, 2H), 2.05-1.93 (m, 5H), 1.45-1.26 (m, 9H)

Example 23 Synthesis and characterization:

W-f4-Cyanobicyclo[2,2,1]heptan-1-yl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d ]pyrrolo[2,3-b/pyridin-2-yl)acetamide

[0259]

[0260] Step A: tert-butyl (4-(chlorocarbonyl)bicyclo[2.2.1]heptan-1-yl)carbamate. To a solution of 4- (( tert- butoxycarbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid (1.00 g, 3.92 mmol) in CH ² Cl ² (5 mL) was added oxalyl chloride (0.75 g, 5.9 mmol) was added at 0 °C dropwise, then DMF (0.1 mL) was added. The mixture was stirred at 0 °C for 1 h. The reaction was concentrated to dryness to provide the title compound (1.05 g, 97.9% yield) as a yellow oil, which was used in the next step without further purification.

[0261] Step B: tert-butyl (4-carbamoylbicyclo[2,2,1]heptan-1-yl)carbamate. To a solution of tert-butyl (4-(chlorocarbonyl)bicyclo[2,2,1]heptan-1-yl)carbamate (1.05 g, 3.84 mmol) in methanol (5 mL) was added ammonia (0.10 g, 5.8 mmol) and stirred at room temperature for 1 h. The reaction was concentrated to dryness to provide the title compound (200 mg, 20.5% yield) as a yellow oil.

[0262] Step C: tert-butyl (4-cyanobicyclo[2,2,1]heptan-1-yl)carbamate and (4-cyanobicyclo[2,2,1]heptan-1-yl)(2,2 tert-butyl ,2)-trifluoroacetyl)carbamate. To a solution of tert-butyl (4-carbamoylbicyclo[2.2.1]heptan-1-yl)carbamate (200 mg, 0.79 mmol), triethylamine (0.031 mL, 2.4 mmol), and CH ² Cl ² (5 mL) at 0 °C was added trifluoroacetic anhydride (248 mg, 1.18 mmol). After the addition was complete, the solution was allowed to warm to room temperature and stirring was continued overnight. The reaction was diluted with CH ² Cl ² (10 mL), washed with saturated aqueous NaHCO3 (5 mL X 2), water (5 mL), brine (3 mL), dried over anhydrous MgSO ⁴ , filtered, and concentrated. to dryness to provide the title compound as a mixture of two compounds (120 mg, 56% yield) as a yellow oil, which was used in the next step without further purification. TLC of the title compound: (petroleum ether:ethyl acetate = 5:1), Rf = 0.4.

[0263] Step D: tert-butyl (4-cyanobicyclo[2,2,1]heptan-1-yl)carbamate. Sodium methoxide (34 mg, 0.63 mmol) was added to a solution of tert-butyl (4-cyanobicyclo[2,2,1]heptan-1-yl)(2,2,2-trifluoroacetyl)carbamate ( 60 mg, 0.18 mmol) and tert-butyl (4-cyanobicyclo[2.2.1]heptan-1-yl)carbamate (60 mg, 0.25 mmol) in methanol (4 mL) at 0 °C (ice/water) and stirred for 3 hours at 0°C The reaction was diluted with ethyl acetate (15ml) and water (10ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10ml X 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness to provide the title compound (30 mg, 70% yield) as a yellow oil, which was used without more purification. TLC of the title compound: (petroleum ether:ethyl acetate = 5:1), Rf = 0.4.

[0264] Step E: 4-aminobicyclo[2,2,1]heptane-1-carbonitrile. To a solution of tert-butyl (4-cyanobicyclo[2,2,1]heptan-1-yl)carbamate (90 mg, 0.38 mmol) was added HCl (4 M in EtOAc, 0.48 mL) and ethyl acetate (4 mL) and stirred at room temperature for 3 h. The reaction was filtered to provide the title compound (50 mg, 96% yield) as a white solid, which was used without further purification. TLC of the title compound: (dichloromethane:methanol = 10:1), Rf = 0.4.

[0265] Step F: W-(4-cyanobicyclo[2,2,1]heptan-1 -yl)-2-(1 -((7r,4r,)-4-(cyanomethyl)cyclohexyl)-1,6 -dihydroimidazo[4,5-a]pyrrolo[2,3-bjpyridin-2-yl)acetamide. A solution of 4-aminobicyclo[2.2.1]heptane-1-carbonitrile (50 mg, 0.29 mmol), 2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo sodium[4,5-a]pyrrolo[2,3-bjpyridin-2-yl)acetate (intermediate 4, 104 mg, 0.290 mmol), PyBrOP (162 mg, 0.348 mmol) and DIPEA (112 mg, 0.869 mmol) in DMF (5ml) was stirred overnight.The reaction was quenched with water (20ml) and extracted with ethyl acetate (3 x 20ml).The combined organic layers were dried over anhydrous MgSO4, filtered and dried. The residue was purified by preparative basic HPLC using a 150 mm x 25 mm, 5 pm DuraShell column (eluent: 20% to 50% (v/v) CH ³ CN and 0.05 H ² O). % NH ³ ) to give the title compound (9 mg, 7% yield) as a white solid MS (ESI): mass calcd for C ²⁶ H ²⁹ N ⁷ O, 455.24, m/z found , 456.2 [M+H]+.1H NMR (400 MHz, DMSO-affe): 11.57 (br s, 1H), 8.50 (s, 1H), 8.45-8.34 ( m, 1H), 7.46 - 7.40 (m, 1H), 6.75 -6.69 (m, 1H), 4.53 -4.42 (m, 1H), 3.96 (s, 2H), 2.59 - 2.56 (m, 2H), 2.41 - 2.30 (m, 3H), 2.12-1 .91 (m, 10H), 1.89-1.81 (m, 2H), 1.78-1.68 (m, 2H), 1.50-1.34 (m, 2H).

Example 24 Synthesis and characterization:

2 -( 1 -( ( í r , 4 ri) -4 -(C ia nomet il)c ic lo hex il) -1 ,6 -d ih id ro im id azo [4 ,5 -a ]p ir ro lo [2 ,3 -b jp ir id in -2 - il) -W -( '(3 -h id ro x io xe ta n -3 -il)met il) ace ta mida

[0266]

[0267] A solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b7pyridin-2- yl)acetate (intermediate 4, 300 mg, 0.835 mmol), 3-(aminomethyl)oxetan-3-ol (86.0 mg, 0.835 mmol), DIPEA (216 mg, 1.67 mmol) and DMF (5 mL) stirred at 0 °C for 1 h.Then PyBrOP (467 mg, 1.00 mmol) was added and the reaction mixture stirred overnight at room temperature.The mixture was quenched with 10 mL of water and quenched. purified by preparative HPLC using a Waters Xbridge Prep OBD C ¹⁸¹⁵⁰ mm X 30 mm, 5 gm column (eluent: water (0.05% v/v ammonium hydroxide)-25 to 55% MeOH, v/v) to give title compound (75 mg, 21% yield) as a white solid MS (ESI): mass calcd for C ²² H ²⁶ N ⁶ O ³ , 422.21, m/z found, 423.2 [M +H]+.1H NMR (400 MHz, DMSO-ds): 511.84 (br s, 1H), 8.49 (s, 1H), 8.46-8.39 (m, 1H), 7, 48 - 7.44 (m, 1H), 6.73 -6.69 (m, 1H), 5.92 (s, 1H), 4.53 -4.43 (m, 1H), 4.42 - 4.35 (m, 4H), 4.06 (br s, 2H), 3.46 - 3.42 (m, 2H), 2.58 (d, J = 6.0 Hz, 2H), 2.42 - 2.26 (m, 2H), 2.08 1.93 (m, 5H), 1.45-1.30 (m, 2H).

Reference Example 25 Synthesis and Characterization:

2-(( 1r,4r)-4- ( 2- (( 1 H -pyrazol-5-yl)methyl)imidazo[4,5-a]pyrrolo[2,3-b7 pyridin-1 ( ⁶ H)- yl)cyclohexyl)acetonitrile

[0268]

[0269] Step A: N- ( 4- ((( 1r,4r)-4-(Cyanomethyl)cyclohexyl)amino)-1 -(phenylsulfonyl)-1 Hpyrrolo/2,3-fo/pyrid¡ n-5-l)-2-(1H-pyrazol-5-yl)acetamide. HATU (696 mg, 1.83 mmol) was added to a solution of 2-((1r,4r)-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b/ pyridin-4-yl)amino)cyclohexyl)acetonitrile (intermediate 2, 500 mg, 1.22 mmol), 2-(1H-pyrazol-5-yl)acetic acid hydrochloride (238 mg, 1.46 mmol), DIPEA (1.2 mL, 6.5 mmol) and DMF (5 mL) and stirred at room temperature for 16 hours. The reaction was concentrated to dryness, water (50 mL) added, and extracted three times with CH ² CL (50 mL X 3). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to provide the title compound (600 mg, 90% yield) as a brown oil. MS (ESI): mass calc. for C ²⁶ H ²⁷ N ⁷ O ³ S, 517.60; m/z found, 518.1 [M+H]+.

[0270] Step B: 2-(( 1r,4r)-4- ( 2- (( 1 H-pyrazol-5-yl)methyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2 ,3-b/pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. A solution of N-(4-(((1r,4r)-4-(cyanomethyl)cyclohexyl)amino)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b/pyridin-5-yl)-2 -(1H-pyrazol-5-yl)acetamide (350 mg, 0.676 mmol) and HOAc (20 mL) was stirred at 100 °C for ¹⁶ hours. The reaction was concentrated to dryness, washed with saturated NaHCO3 (50ml) and extracted with chloromethane (50ml X 2). The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to provide the title compound (300 mg, ^6-8 % yield) as a yellow oil. MS (ESI): mass calc. for C ²⁶ H ²⁵ N ⁷ O ² S, 499.59; m/z found, 499.9 [M+H]+.

[0271] Step C: 2-((1 r,4r)-4- ( 2- (( 1 H-pyrazol-5-yl)methyl)imidazo[4,5-a(|pyrrolo[2,3-b /pyridine-1( ^6H )-yl)cyclohexyl)acetonitrile The title compound (63.6 mg, 29% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2-(( 1r,4r)-4-(2-((1H-Pyrazol-5-yl)methyl)-6-(phenylsulfonyl)imidazo[4,5-a(|pyrrolo[2,3-b7pyridin-1(6H)- yl)cyclohexyl)acetonitrile (300 mg, 0.600 mmol) in place of 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5 -a(|pyrrolo[2,3-b7pyridin-2-yl)-N-72-hydroxy-2-methylpropyl)acetamide Purification was performed on preparative HPLC using the following conditions: 150 mm x 25 mm Gemini column, 10 gm (eluent: water (0.05% v/v ammonium hydroxide)-20 to 50% v/v ACN). MS (ESI): mass calc. for C ²⁰ H ²¹ N ⁷ , 359, 19, m/z found, 360.1 [M+H]+.1H NMR (400 MHz, DMSO-ds): 511.80 (br s, 1H), 8.49 (s, 1H), 7.61 - 7.54 (m, 1H), 7.42 (d, J = 3.1 Hz, 1H), 6.64 (d, J = 3.5 Hz, 1H) , 6.13 - 5.93 (m, 2H), 4.62 -4.49 (m, 1H), 4.36 (s, 2H), 2.55 - 2.48 (m, 2H), 2 .33 - 2.15 (m, 2H), 2.03 1.82 (m, 3H), 1.71-1.53 (m, 2H), 1.5-1.18 (m, 2H).

Example 26 Synthesis and characterization:

2-((1r,4r)-4-(2-(2-(4-morpholinopiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d|pyrrolo[2,3-fo]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile

[0272]

[0273] A solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d|pyrrolo[2,3-b/pyridin-2 -yl)acetate (Intermediate 4, 200 mg, 0.557 mmol), 4-(piperidin-4-yl)morpholine (94.8 mg, 0.557 mmol), DIPEA (144 mg, 1.11 mmol), and DMF (5 mL ) was stirred at 0 °C for 1 h. PyBrOP (311 mg, 0.668 mmol) was then added and stirred at room temperature overnight. The mixture was quenched with 10 mL of water and purified by preparative acid HPLC using a 150 mm x 30 mm Boston Green ODS column, 5 pm (eluent: water (0.05%) HCl-0 to 30% ACN. %, v/v) and then by preparative basic HPLC using a Kromasil 150 mm X 25 mm, 10 pm column (eluent: water (0.05% ammonium hydroxide v/v)-10 to 40% ACN, v/ v) to provide the title compound (25 mg, 9% yield) as a white solid. MS (ESI): mass calc. for C ²⁷ H ³⁵ N ⁷ O ² , 489.29; m/z found, 490.3 [M+H]+. 1H NMR (400 MHz, DMSO-da): 511.85 (br s, 1H), 8.51-8.47 (m, 1H), 7.48-7.44 (m, 1H), 6.72 -6.68 (m, 1H), 4.42 -4.29 (m, 2H), 4.25 (d, J = 8.4 Hz, 2H), 4.16 -4.07 (m, 1H ), 3.59 - 3.52 (m, 4H), 3.15 - 3.05 (m, 1H), 2.69 - 2.63 (m, 1H), 2.58 (d, J = 6 0 Hz, 3H), 2.47-2.41 (m, 5H), 2.07-1.90 (m, 6H), 1.85-1.74 (m, 2H), 1.42- 1.27 (m, 3H), 1.27-1.13 (m, 1H ).

Example 27 Synthesis and characterization:

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d|pyrrolo[2,3-b/pyridin-2-yl)-N-( (1r,4r)-4-(hydroxymethyl)cyclohexyl)acetamide

[0274]

[0275] A solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d|pyrrolo[2,3-fo]pyridin-2 -yl)acetate (Intermediate 4, 200 mg, 0.557 mmol), ((1r,4r)-4-aminocyclohexyl)methanol (71.9 mg, 0.557 mmol), PyBrOP (311 mg, 0.668 mmol), DIPEA (144 mg , 1.11 mmol) and DMF (10 mL) were stirred at room temperature overnight. The mixture was quenched with 20 mL of water and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated to dryness. The residue was purified by preparative basic HPLC using a 150 mm x 25 mm DuraShell column, 5 pm (eluent: 13% to 43% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (32.7 mg, 13% yield) as a white solid. MS (ESI): mass calc. for C ²⁵ H ³² N ⁶ O ² , 448.26; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, DMSO-da): 5 11.87 - 11.76 (m, 1H), 8.52 -8.42 (m, 1H), 8.25 - 8.14 (m, 1H) , 7.47 - 7.42 (m, 1H), 6.73 - 6.65 (m, 1H), 4.55 -4.24 (m, 3H), 3.93 (br s, 2H), 3.21 - 3.11 (m, 2H), 2.63 - 2.55 (m, 2H), 2.36 - 2.25 (m, 2H)), 2.08-1.88 (m, 4H), 1.87-1.75 (m, 2H), 1.77-1.66 (m, 2H), 1.44-1.10 (m, 5H), 0.98 - 0.78 ( m, 3H).

Reference Example 28 Synthesis and Characterization:

2 -(1 -( ( 1 r ,4 r ) -4 -(cyanomethyl) cyclohex yl) -1 ,6 -d ih idro imidazo [4 ,5 -d |p ir ro lo [2 ,3 -b /p ir id in -2 - il) -N -c ic lo hex ila ce ta m id a

[0276]

[0277] A solution of sodium 2-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b/pyridin-2 -yl)acetate (intermediate 4, 200 mg, 0.557 mmol), cyclohexylamine (55.2 mg, 0.557 mmol), PyBrOP (311 mg, 0.668 mmol), DIPEA (144 mg, 1.11 mmol), and DMF was stirred (3ml) at room temperature overnight.The mixture was quenched with 20ml water and extracted with EtOAc (3 x 20ml).The combined organic layers were dried over anhydrous MgSO4 and concentrated to dryness.The residue was purified by preparative basic HPLC using a 150 mm x 25 mm, 5 gm Gemini column (eluent: 12% to 42% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to give the title compound (37.5 mg, 16% yield) as a white solid MS (ESI): mass calcd for C ²⁴ H ³⁰ N ⁶ O, 418.25, m/z found, 419.2 [M +H]+.1H NMR (400 MHz, DMSO-afe): 512.55 (br s, 1H), 8.81 (s, 1H), 8.56-8.47 (m, 1H), 7, 77 - 7.70 (m, 1H), 6.93 (br s, 1H), 4.64 (br s, 1H), 4.29 (s, 2H), 2.61 (d , J = 5.7 Hz, 2H), 2.43 - 2.26 (m, 2H), 2.14-1.95 (m, 4H), 1.83 1.75 (m, 2H), 1 .72-1.69 (m, 2H), 1.61-1.51 (m, 1H), 1.49-1.35 (m, 2H), 1.34-1.07 (m, 7H) .

Example 29 Synthesis and characterization:

2-(1-((fr,4rf-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-bjpyridin-2-yl)-W-^2-hydroxyethyl )acetamide

[0278]

[0279] A solution of sodium 2-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b/pyridin-2 -yl)acetate (intermediate 4, 300 mg, 0.835), 2-aminoethanol (51.0 mg ^, 0.835 mmol), DIPEA (216 mg, 1.67 mmol), and ^dMf (5 mL) were stirred at 0° C for 1 hour PyBrOP (311 mg, 0.668 mmol) was then added and stirred at room temperature overnight Reflected on a 150 mm X 25 mm DuraShell column, 5 gm (eluent: water ( 0.05% ammonia hydroxide v/v)-ACN 14 to 44%, v/v) to give the title compound (78 mg, 24% yield) as a yellow solid MS (ESI): mass Calcd for C ²⁰ H ²⁴ N ⁶ O ² , 380.20, m/z found, 381.2 [M+H]+.

1H NMR (400 MHz, DMSO-ds): 11.85 (br s, 1H), 8.50 (s, 1H), 8.35-8.29 (m, 1H), 7.49-7, 45 (m, 1H), 6.74 - 6.70 (m, 1H), 4.79 -4.72 (m, 1H), 4.56 -4.45 (m, 1H), 4.00 ( s, 2H), 3.49 - 3.42 (m, 2H), 3.22 - 3.15 (m, 2H), 2.59 (d, J = 6.0 Hz, 2H), 2.43 - 2.27 (m, 2H), 2.07-1.93 (m, 5H), 1.46-1.33 (m, 2H).

Example 30 Synthesis and characterization:

N-((1-((fr,4r7-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-bjpyridin-2-yl)methyl)benzimidamide

[0280]

[0281] Step A: N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2, 3-b/pyridin-2-yl)methyl)benzimidamide A solution of 2-((1r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-a(]pyrrolo [2,3-b/pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 8, 49 mg, 0.11 mmol), benzimidamide (42 mg, 0.27 mmol), K ² CO ³ (85 mg , 0.62 mmol) and DMF (2 mL) was stirred at room temperature for 15 h. LCMS showed a small amount of 2-(( 1r,4r)-4-(2-(chloromethyl)-6-( phenylsulfonyl)imidazo[4,5-a(]pyrrolo[2,3-b/pyridin-1(6H)-yl)cyclohexyl)acetonitrile, whereupon more benzimidamide (16 mg), K ² CO ³ (45 mg, 0.33 mmol) and DMF (1 mL), and the mixture was stirred at room temperature overnight.After filtering off the solid, the filtrate was concentrated to dryness.The residue of the filtrate was purified by flash column chromatography to provide the title compound (50 mg, 86% yield) MS (ESI): mass calcd for C ³⁰ H ²⁹ N ⁷ O ² S, 551.21; m/z found, 552.3 [M+H]+.

[0282] Step B: N-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-bjpyridin-2- yl)methyl)benzimidamide A mixture of W-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo [2,3-b]pyridin-2-yl)methyl)benzimidamide (50 mg, 0.091 mmol), 1 M NaOH (0.20 mL, 0.20 mmol), MeOH (0.7 mL), and THF (0 0.7 mL) was stirred at room temperature for 18 h and concentrated in vacuo The residue was purified by reverse phase HPLC (10-90% CH ³ CN in H ² O, 0.1% ^tFA ) to give a clear oil. This material was dissolved in EtOAc and washed with aq. NaHCO3. The aqueous layer was extracted with EtOAc (x 4). The combined extracts were dried over Na2SO4, filtered, and concentrated to give the title compound as an off-white solid (29 mg, 78% yield) MS (ESI): mass calcd for C ²⁴ H ²⁵ N ⁷ , 411.22, m/z found, 412.4 [M+H]+.

1H NMR (400 MHz, CDCla) = 9.77 (br s, 1H), 8.70 (s, 1H), 7.70 (br d, J = 7.1 Hz, 2H), 7.57 - 7.44 (m, 3H), 7.41 (br s, 1H), 6.74 (d, J = 3.0 Hz, 1H), 5.08 (br s, 2H), 4.91 -4 .77 (m, 1H), 2.58 - 2.45 (m, 2H), 2.40 (d, J = 6.6 Hz, 2H), 2.16 (br d, J = 11.6 Hz , 3H), 2.12-1.98 (m, 2H), 1.59-1.42 (m, 2H).

Reference Example 31 Synthesis and Characterization:

2-(( 1r,4r)-4- ( 2- ( 4-chloro-1 H -pyrazol-3-yl)imidazo[4,5-a(]pyrrolo[2,3-bjpyridin-1 (6H)- yl)cyclohexyl)acetonitrile

[0283]

[0284] Step A: 2-((1r,4r)-4-(2-(4-chloro-1H-pyrazol-3-yl)-6-(phenylsulfonyl)imidazo[4,5-a(]pyrrolo [2,3-bjpyridin-1( 6H) -yl)cyclohexyl)acetonitrile To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl )-1H-pyrrolo[2,3-b/pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 165 mg, 0.375 mmol) and 4-chloro-3-formylpyrazole (91 mg, 0.70 mmol) as solids DMSO (1.87 mL), MeOH (1.87 mL) and distilled water (1.0 mL) were then added Then sodium hydrosulfite (147 mg, 0.847 mmol) was added as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100 °C for 7 h. The reaction was cooled to room temperature and poured into 30 mL of water, resulting in the formation of a precipitate. The mixture was stirred for 15 minutes and then the yellow solids were collected by filtration and dried under high vacuum for 1 hour.The residue was purified by flash column chromatography to provide the title compound (122 mg, 62.5% yield). MS (ESI): mass calc. for C25H22ClN7O2S, 519.12; m/z found, 521.8 [M+H]+.

[0285] Step B: 2-(( 1r,4r)-4-(2-(4-chloro-1H-pyrazol-3-yl)imidazo[4,5-c/]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile. The title compound was prepared using analogous conditions to those described in Example 1, Step B using 2- (( 1r,4r) -4-(2-(4-chloro-1H-pyrazol-3-yl)-6 -(phenylsulfonyl)imidazo[4,5-a(]pyrrolo[2,3-bjpyridin-1(6H)-yl)cyclohexyl)acetonitrile (122 mg, 0.24 mmol) in place of 2-(1-(( 1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-bjpyridin-2-yl)-W-(2- hydroxy-2-methylpropyl)acetamide and purified by basic HPLC: using a 150 mm x 30 mm Waters Xbridge Prep OBD C ¹⁸ column, 5 pm (0-100% aqueous NH ⁴ OH/ACN eluent (10 min) to give the title compound (28 mg, 31% yield).MS (ESI): mass calculated for C19H1sClN7, 379.13, m/z found, 381.9 [M+H]+.1H ^r M ⁿ (400 MHz, CDCh) 5 10.12 (s, 1H), 8.91 (s, 1H), 7.77 (s, 1H), 7.43 (d, J = 3.5 Hz, 1H), 6.78 ( d, J = 3.5 Hz, 1H), 4.74 (s, 1H), 2.68 - 2.47 (m, 2H), 2.40 (d, J = 6.2 Hz, 2H), 2.25-1.94 (m, 6H), 1.41 (q, J =12.6, 11.5Hz, 2H).

Reference Example 32 Synthesis and Characterization:

N -((3 R ,5 fi) -A daman ta n -1 - il) -2 -(1 -( (1 r ,4 r ) -4 -(c ia nome ti l) c ic lo hex il) -1 ,6 -d ih id ro im id azo [4 ,5 -a ( ]p ir ro lo [2 ,3 -b jp ir id in -2 -il)ace ta mid a

[0286]

[0287] A solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b/pyridin- 2-yl)acetate (intermediate 4, 200 mg, 0.557 mmol), (3s,5s,7s)-adamantan-1-amine hydrochloride (104 mg, 0.557 mmol), DIPEA (144 mg, 1.11 mmol) and DMF (5 mL) was stirred at 0 °C for 1 hour PyBrOP (311 mg, 0.668 mmol) was then added and stirred at room temperature overnight The mixture was quenched with 10 mL of water and purified by preparative basic HPLC using a Kromasil 150 mm x 25 mm, 10 gm column (eluent: water (0.05% v/v ammonium hydroxide)-30 to 60% ACN) to give the title compound (50 mg, 19% yield) as a white solid MS (ESI): mass calcd for C ²⁸ H ³⁴ N ⁶ O, 470.28, m/z found, 471.3 [M+H]+ 1H NMR (400 MHz, DMSO-ds): 11.84 (br s, 1H), 8.49 (s, 1H), 7.86 (br s, 1H), 7.47-7.44 (m, 1H ), 6.71 - 6.88 (m, 1H), 4.51 - 4.37 (m, 1H), 3.93 (s, 2H), 2.61 (d, J = 5.6 Hz, 2H), 2.38 - 2.31 (m, 1H) , 2.04-1.92 (m, 15H), 1.64-1.59 (m, 6H), 1.47-1.34 (m, 2H).

Reference Example 33 Synthesis and Characterization:

2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b7pyridin-2-yl)-W-(^( 1r,4r)-4- hydroxycyclohexyl)acetamide

[0288]

[0289] A solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-bjpyridin-2-yl )acetate (Intermediate 4, 200 mg, 0.557 mmol), (1r,4r)-4-aminocyclohexanol (64.1 mg, 0.557 mmol), PyBrOP (311 mg, 0.668 mmol), DIPEA (144 mg, 1.11 mmol ) and DMF (10 mL) was stirred overnight. The mixture was quenched with 20 mL of water and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated to dryness. The residue was purified by preparative basic HPLC using a 150 mm x 25 mm, 5 gm DuraShell column (eluent: 15% to 45% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (27.9 mg, 11% yield) as a white solid. MS (ESI): mass calc. for C ²⁴ H ³⁰ N ⁶ O ² , 434.24; m/z found, 435.2 [M+H]+. 1H NMR (400 MHz, DMSO-cfe): 511.85 (br s, 1H), 8.49 (s, 1H), 8.22-8.19 (m, 1H), 7.47-7.45 (m, 1H), 6.71 (br s, 1H), 4.59 (d, J = 4.4 Hz, 1H), 4.55 -4.39 (m, 1H), 3.95 (s , 2H), 2.60 (d, J = 5.7 Hz, 2H), 2.42-2.33 (m, 2H), 2.08-1.92 (m, 5H), 1.89- 1.71 (m, 5H), 1.48-1.31 (m, 2H), 1.31-1.12 (m, 5H).

Example 34 Synthesis and characterization:

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b/pyridin-2-yl)-W- ('(1-hydroxycyclobutyl)methyl)acetamide

[0290]

[0291] A solution of sodium 2-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)acetate (intermediate 4, 300 mg, 0.835 mmol), 1-(aminomethyl)cyclobutanol (84.4 mg, 0.835 mmol), DIPEA (216 mg, 1.67 mmol) and DMF (5 mL) was stirred at 0 °C for 1 h. PyBrOP (467 mg, 1.00 mmol) was then added and stirred at room temperature overnight, then quenched with 10 mL of water. The reaction was purified by preparative basic HPLC using a Kromasil 150 mm x 25 mm column, 10 pm (eluent: water (0.05% v/v ammonium hydroxide)-9 to 39% ACN, v/v) to give the title compound (90 mg, 26% yield) as a white solid MS (ESI): mass calcd for C ²³ H ²⁸ N ⁶ O ² , 420.23, m/z found, 421.2 [M+H]+ 1H NMR ( 400 MHz, DMSO-cfe): 511.58 (br s, 1H), 8.50 (s, 1H), 7.94 - 7.85 (m, 1H), 7.46 - 7.40 (m, 1H), 6.75 -6.70 (m, 1H), 4.89 (br s, 1H), 4.57 - 4.47 (m, 1H), 4.04 (s, 2H), 3, 27 (d, J = 6.0 Hz, 2H), 2.55 (d , J = 6.0 Hz, 2H), 2.45 - 2.31 (m, 2H), 2.10-1.88 (m, 9H), 1.71 -1.60 (m, 1H), 1.54-1.35 (m, 3H).

Example 35 Synthesis and characterization:

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-djpyrrolo[2,3-bjpyridin-2-yl)-W-^pyrazin-2-ylmethyl)acetamide

[0292]

[0293] To a 10 mL microwave vial was added 2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b Sodium /pyridin-2-yl)acetate (intermediate 4, 154 mg, 0.429 mmol) as a solid followed by dissolving in DMF (1.7 mL) PyBOP (352 mg, 0.676 mmol) was added in one portion and immediately a canary yellow color formed The resulting solution was stirred for 15 min before DIPEA (0.295 mL, 1.71 mmol) was added, followed by 2-aminomethylpyrazine (102 mg, 0.935 mmol) and stirred at room temperature for 2 days The reaction was added to water (20 mL) which resulted in the formation of a precipitate.The solids were collected by filtration.The filtrate was extracted with EtOAc and CH ² Cl ² and the organic layers were combined and concentrated to The residue was purified by basic HPLC: using a Waters Xbridge Prep OBD C ¹⁸ 50 mm X 100 mm, 5 mm (eluent = 0-100% aqueous NH ⁴ OH/ACN (10 min)) to give the title compound (eleven mg, 6% yield) as a fluffy white powder. m S (ESI): mass calc. for C ²³ H ²⁴ N ⁸ O, 428.21; m/z found, 429.0 [M+H]+. 1H r Mn (500 mHz, CDCh): 10.33 (s, 1H), 8.72 (s, 1H), 8.59 (d, J = 1.0 Hz, 1H), 8.51 - 8.43 (m, 2H), 7.47 - 7.37 (m, 1H), 6.72 (m, J = 3.5, 1.9 Hz, 1H), 4.73 -4.53 ( m, 3H), 4.10 (s, 2H), 2.53 (s, 2H), 2.41 (d, J = 6.5 Hz, 2H), 2.26 - 2.12 (m, 2H ), 2.12-1.93 (m, 3H), 1.57-1.37 (m, 2H).

Example 36 Synthesis and characterization:

N-((1 H-imidazol-2-yl)methyl)-2-(1-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo [2,3-b]pyridin-2-yljacetamide

[0294]

[0295] To a 10 mL microwave vial was added 2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3- Sodium bjpyridin-2-yl)acetate (intermediate 4, 136 mg, 0.378 mmol) as a solid followed by dissolving in DMF (1.5 mL).PyBOP (304 mg, 0.584 mmol) was added in one portion.The solution stirred for 15 min before addition of DIPEA (0.261 mL, 1.51 mmol), followed by (1H-imidazol-2-yl)methanamine dihydrochloride (151 mg, 0.870 mmol) and stirred at room temperature for 72 h The reaction was added to saturated NaHCO3 (20 mL) resulting in the formation of a precipitate The solids were collected by filtration The solids were solubilized in EtOAc and the aqueous phase was extracted with EtOAc and CH ² Cl ² and organic phases were combined, dried over anhydrous Na2SO4 and concentrated to dryness The residue was purified by basic HPLC: Waters Xbridge Prep OBD C ¹⁸ 150 mm x 30 mm 5 qm, eluent 0-100% NH ⁴ OH aqueous/ACN (10 min) pa to provide the title compound (6 mg, 4% yield). MS (ESI): mass calc. for C ²² H ²⁴ N ⁸ O, 416.21; m/z found, 418.0 [M+H]+. 1H NMR (500 MHz, CD ³ OD): 58.54 (s, 1H), 7.48 (d, J = 3.5 Hz, 1H), 7.09 -6.92 (m, 2H), 6 .84 (d, J = 3.6 Hz, 1H), 4.74 -4.37 (m, 4H), 2.69 -2.41 (m, 3H), 2.20-1.97 (m , 5H), 1.55-1.38 (m, 2H), 1.38-1.24 (m, 3H).

Example 37 Synthesis and characterization:

2-(1-((fr,4rf-4-(Cyanomethyl)cyclohexyl)-1,6-d¡h¡d¡dro¡m¡dazo[4,5-c/|p¡rrolo[2,3-b/ p¡r¡d¡n-2-¡l)-A/-('(7fí,3fíj-3-hydroxycyclobutyl)acetamide

[0296]

[0297] A solution of sodium 2-(1-((fr,4rf-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-bjpyridin-2-yl )acetate (intermediate 4, 300 mg, 0.835 mmol), (7R,3Rj-3-aminocyclobutanol (72.7 mg, 0.835 mmol), DIPEA (216 mg, 1.67 mmol) and DMF (5 mL) were shaken at 0 °C for 1 h. PyBrOP (467 mg, 1.00 mmol) was then added and stirred at room temperature overnight. The mixture was quenched with 10 mL of water. The reaction was purified by preparative basic HPLC using a Kromasil 150 mm X 25 mm, 10 qm column (eluent: water (0.05% v/v ammonium hydroxide)-22 to 32% ACN, v/v) and by prep TLC (CH ² C ² MeOH = 10:1) to give the title compound (36 mg, 11% yield) as a white solid MS (ESI): mass calcd for C ²² H ²⁶ N ⁶ O ² , 406.21, m/z found, 407.2 [M+H]+.1H NMR (400 MHz, DMSO-afe): 511.83 (br s, 1H), 8.59 (d, J = 6.8 Hz, 1H), 8 .49 (s, 1H), 7.48 - 7.43 (m, 1H), 6.73 -6.68 (m, 1H), 5.03 (d, J = 5.6 Hz, 1H), 4.56 -4.4 3 (m, 1H), 4.34 -4.25 (m, 1H), 4.24 -4.14 (m, 1H), 3.95 (s, 2H), 2.59 (d, J = 5.6 Hz, 2H), 2.43-2.26 (m, 2H), 2.21-1.90 (m, 9H), 1.45-1.30 (m, 2H).

Example 38 Synthesis and characterization:

2-(1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-bjpyridin-2-yl)-W-('1 -methyl-1 H-pyrazol-4-yl)acetamide

[0298]

To a solution of 2-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b/pyridin-2-yl) sodium acetate (Intermediate 4, 100 mg, 0.278 mmol) and 1-methyl-1H-pyrazol-4-amine (54.0 mg, 0.557 mmol) in DMF (0.8 mL), PyBrOP (217 mg, 0.417 mmol) and DIPEA (0.144 mL, 0.835 mmol) and the mixture was stirred at room temperature overnight.The DMF was removed under reduced pressure and the residue was purified by flash column chromatography (50-100% EtOAc/heptanes , then 10% MeOH/DCM) and subsequently by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 mm X 30 mm column (eluent 10 - 90% CH ³ CN in water, 0.1% TFA) to provide the product as TFA salt. This material was dissolved in 10% MeOH in CH ² CI ² and passed through a 500 mg carbonate column SILICYCLE SPE-R66030B-03P (SiliaBond Acid Scavenger Solid Phase Extraction cartridge) to remove TFA. and provide the title compound (34 mg, 29% yield) as a white solid. MS (ESI): mass calc. for C ²² H ²⁴ N ⁸ O, 416.21; m/z found, 417.3 [M+H]+. 1H NMR (400 MHz, CDCta) 5 = 12.77 (br s, 1H), 11.24 (br s, 1H), 7.94 (s, 1H), 7.89 (br s, 1H), 7 .46 (s, 1H), 7.29 - 7.20 (m, 1H), 6.74 (br s, 1H), 4.85 -4.65 (m, 1H), 4.23 (s, 2H), 3.85 (s, 3H), 2.80-2.55 (m, 1H), 2.45 (d, J = 6.6 Hz, 2H), 2.32-1.98 (m , 6H), 1.62-1.44 (m, 2H).

Reference Example 39 Synthesis and Characterization:

W-(4-cyanobenzyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d|pyrrolo[2,3-b]pyridin- 2-yl)acetamide

[0299]

[0300] To a solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d|pyrrolo[2,3-b]pyridin- 2-yl)acetate (Intermediate 4, 100 mg, 0.278 mmol) and 4-(aminomethyl)benzonitrile (73.6 mg, 0.557 mmol) in DMF (0.8 mL) were added PyBrOP (217 mg, 0.417 mmol) and DIPEA (0.144 mL, 0.835 mmol) and stirred at room temperature for 87 h. The DMF was removed under reduced pressure and the residue was purified by flash column chromatography and reverse phase HPLC using a Phenomenex Luna C ¹⁸ 100 mm X 30 mm column, 5 pm (mobile phase gradient 5-95% ACN in H ² O (both with 0.1 % TFA), v/v) to provide the product as the TFA salt. This material was dissolved in MeOH and passed through a 500 mg carbonate column SILICYCLE SPE-R66030B-03P (SiliaBond acid scavenger solid phase extraction cartridge) to remove the TFA to provide the title compound (47 mg, 37% yield) as a white solid. MS (ESI): mass calc. for C ²⁶ H ²⁵ N ⁷ O, 451.21; m/z found, 452.1 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 5 = 8.53 (s, 1H), 7.74-7.68 (m, 2H), 7.55-7.49 (m, 2H), 7.49 - 7.45 (m, 1H), 6.83 (d, J =4.0 Hz, 1H), 4.52 -4.46 (m, 3H), 4.18 -4.12 (m, 1H ), 2.54 (d, J =5.6 Hz, 4H), 2.13-1.98 (m, 6H), 1.48-1.32 (m, 2H).

Reference Example 40 Synthesis and Characterization:

1 -((1 -((1r,4r)-4-(cyanoniethyl)cyclohexyl)-1,6-dihydroinudazo[4,5-d|pyrrolo[2,3-b]pyridin-2-yl)methyl)urea

[0301]

[0302] Potassium cyanate (141 mg, 1.74 mmol) was added to a solution consisting of 2- (( 1r,4r)-4- ( 2- (aminomethyl)imidazo[4,5-d|pyrrolo[ 2,3-d]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (Intermediate 5, 200 mg, 0.580 mmol), NaHCO3 (49 mg, 0.58 mmol), dioxane (3ml) and water (0.75 ml) and stirred for 2 h at 90 °C. The mixture was diluted with water (10ml) and extracted with ethyl acetate (20ml X 2). The combined organic extracts were evaporated to dryness and purified by preparative HPLC using a Boston Green ODS 150 mm x 30 mm 5 pm column (eluent: 5% to 30% (v/v) CH ³ CN and aqueous HCl ( 0.006N)). The pure fractions were collected and the volatile organic components were removed under reduced pressure. The remaining aqueous mixture was treated with saturated aqueous NaHCO3 until pH = 7-8 and extracted with a mixture of CH ² Cl ² and ethyl acetate (1:1) (50 ml X 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The product was suspended in water (10 mL), the mixture was frozen using dry ice/acetone and lyophilized to dryness to give the title compound (35 mg, 17% yield) as a white solid. MS (ESI): mass calc. for C ¹⁸ H ²¹ N ⁷ O, 351.18; m/z found, 352.2 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 511.87 (s, 1H), 8.53 (s, 1H), 7.50-7.43 (m, 1H), 6.72 (s, 1H) , 6.65 -6.57 (m, 1H), 5.70 (s, 2H), 4.66 -4.51 (m, 3H), 2.58 (d, J = 6.0 Hz, 2H ), 2.40-2.27 (m, 2H), 2.08-1.87 (m, 5H), 1.48-1.33 (m, 2H).

Reference Example 41 Synthesis and Characterization:

2-((7r,4r)-4-(2-(Thiazol-4-ylmethyl)imidazo[4,5-a(]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0303]

[0304] Step A: N-(4-((( 7r,4r)-4-(cyanomethyl)cyclohexyl)amino)-1 -(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5- yl)-2-(thiazol-4-yl)acetamide. HATU (2.12 g, 5.58 mmol) was added to a mixture containing 2-((7r,4r)-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3- b]pyridine -4-yl)amino)cyclohexyl)acetonitrile (Intermediate 2, 1.14 g, 2.78 mmol), 2-(thiazol-4-yl)acetic acid (400 mg, 2.79 mmol), DIPEA (722 mg, 5.59 mmol) and DMF (10 mL) at 0 °C (ice/water) and stirred at room temperature for 2 hours. The reaction was partitioned between EtOAc (100ml) and water (100ml), the aqueous layer was extracted with ethyl acetate (50ml X 3) and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness. . The residue was purified by flash column chromatography to provide the title compound (1.5 g, 95% yield) as a yellow solid. MS (ESI): mass calc. for C ²⁶ H ²⁶ N ⁶ O ³ S ² , 534.65; m/z found, 534.9 [M+H]+.

[0305] Step B: 2-((7r,4r)-4-(6-(phenylsulfonyl)-2-(thiazol-4-ylmethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1( 6H)-yl )cyclohexyl)acetonitrile. Acetic acid (5 mL) was added to W-('1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo [2,3-b]pyridin-2-yl)-2-(thiazol-4-yl)acetamide (500 mg, 0.935 mmol) and heated at 130 °C for 6 hours Saturated NaHCOa solution (30 ml) to the reaction mixture and extracted with CH ² Cl ² (30 ml X 4).The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness.The residue was purified by flash column chromatography to give title compound (100 mg, 20% yield) MS (ESI): mass calcd for C ²⁶ H ²⁴ N ⁶ O ² S ² , 516.14, m/z found, 517.1 [M+H ]+.

[0306] Step C: 2-((7r,4r)-4-(2-(Thiazol-4-ylmethyl)imidazo[4,5-c/jpyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile. The title compound (85 mg, 27% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2-((7r,4r)-4-(6-(phenylsulfonyl)-2-( thiazol-4-ylmethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (180 mg, 0.348 mmol) in place of 2-(1-( (7r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl)-W- (2-hydroxy-2-methylpropyl)acetamide The title compound was purified by HPLC using a Phenomenex Gemini 150 mm X 25 mm, 10 gm (eluent: CH ³ CN in H ² O (0.05% ammonia soln. ) from 20 to 50%, v/v) MS (ESI): mass calcd for C ²⁰ H ²⁰ N ⁶ S, 376.2, m/z found, 377.2 [M+H]+ 1H NMR (400 MHz, DMSO-da): 11.80 (s, 1H), 9.03 (d, J = 1.6 Hz, 1H), 8.49 (s, 1H), 7.51 (s , 1H), 7.44 - 7.40 (m, 1H), 6.68 -6.62 (m, 1H), 4.62 -4.53 (m, 3H), 2.55 - 2.51 (m, 2H), 2.35-2.20 (m, 2H), 2.02-1.94 (m, 1H), 1.96-1.86 (m, 2H), 1.75-1 .58 (m, 2H), 1.37-1.20 (m, 2H).

Reference Example 42 Synthesis and Characterization:

2-((1 S,4f)-4-(2-(2-((S)-3-Hydroxypyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-a(]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0307]

[0308] A solution of sodium 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-¿>]pyridin- 2-yl)acetate (Intermediate 4, 200 mg, 0.557 mmol), (S)-pyrrolidin-3-ol (48.5 mg, 0.557 mmol), DiPeA (144 mg, 1.11 mmol) and DMF (5 mL) was stirred at 0 °C for 1 h. Next, PyBrOP (311 mg, 0.668 mmol) was added and stirred at room temperature for 4 h. The mixture was quenched with 10 ml of water and extracted with CH ² Cl ² (2 x 10 ml). The water layer was purified by preparative acid HPLC using a 150 mm x 30 mm, 5 gm Boston Green ODS column (eluent: water (0.05%) HCl-5-35% ACN, v/v). , and the organic layer was purified by preparative acid HPLC using a 150 mm x 30 mm, 5 gm Boston Green ODS column (eluent: water (0.05%) HCl-11 to 41% ACN, v/v ). Fractions containing the title compound were combined and repurified by preparative basic HPLC using a 150 mm x 25 mm, 5 gm DuraShell column (eluent: water (0.05% v/v ammonium hydroxide)-ACN from 14% to 44%, v/v). Finally, the title compound was further purified by preparative TLC (CH ² Cl ² :MeOH = 10:1) to give the compound (10 mg, 4% yield) as a white solid. MS (ESI): mass calc. for C ²² H ²⁶ N ⁶ O ² , 406.2; m/z found, 407.2 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 5 11.84 (br s, 1H), 8.49 (s, 1H), ^{7 , 4 9-7 , 4 4} (m, ^1H ), 6.74 - ^{6 , 6 8} (m, 1H), 5.13 - 4.96 (m, 1H), 4.47 - 4.25 (m, 2H), 4.21 - 4.16 (m, 1H), 4.16 - 4.11 (m, 1H), 3.78 - 3.60 (m, 2H), 3.31 - 3.28 (m, 1H), 2.58 (d, J = 5.6 Hz, 2H), 2.42-2.25 (m, 2H), 2.11-1.72 (m, ^8H ), 1.45-1.28 (m, 2H).

Reference Example 43 Synthesis and Characterization:

2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-alpyrrolo[2,3-b]pyridin-2-yl)-W-(2- (pyridin-4-yloxy)ethyl)acetamide

[0309]

[0310] To a solution of sodium 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin- 2-yl)acetate (Intermediate 4, 70 mg, 0.19 mmol) and 2-(pyridin-4-yloxy)ethanamine (54 mg, 0.39 mmol) in DMF (2 mL) were added PyBOP (152 mg, 0.292 mmol) and DIPEA (0.101 mL, 0.584 mmol) and stirred at room temperature for 18 h. The reaction was concentrated to dryness and the residue was purified by reverse phase acid HPLC using a Varian Pursuit XRs5 Diphenyl 100 X 30 mm column (eluent: 10-90% CH ³ CN in H ² O, 0.1% TFA). The product was dissolved in n-BuOH and saturated NaHCO3 (aq). The organic layer was separated and the aqueous layer was extracted with a 1:1 mixture of n- BuOH and CH ² Cl ² . The combined organic layers were dried over anhydrous MgSO ⁴ , filtered, concentrated to dryness, and purified by flash column chromatography and again by reverse phase acidic HPLC using a Varian Pursuit XRs5 Diphenyl 100 X 30 mm column (eluent: 10 - 90% CH ³ CN in H ² O, 0.1 % TFA) to give the title compound which was still impure. The title compound was then dissolved in n- BuOH and saturated NaHCO ³ (aq). The organic layer was separated and the aqueous layer was extracted with n -BuOH then EtOAc. The extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was dissolved in 10% MeOH in CH ² Cl ² and filtered through a syringe filter. The filtrate was concentrated to dryness to provide the title compound. (18mg, 20% yield). MS (ESI): mass calc. for C ²⁵ H ²⁷ N ⁷ O ² , 457.2; m/z found, 458.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 5 = 8.52 (s, 1H), 8.32 (d, J =5.6 Hz, 2H), 7.48 (d, J =3.5 Hz, 1H), 6.97 (d, J =6.1 Hz, 2H), 6.81 (d, J =3.5 Hz, 1H), 4.51 (br s, 1H), 4.18 (t , J =5.1 Hz, 2H), 3.67 (t, J =5.1 Hz, 2H), 2.53 (br s, 2H), 2.44 (d, J = 6.1 Hz, 2H), 2.11-1.99 (m, ^6H ), 1.47-1.34 (m, 3H).

Reference Example 44 Synthesis and Characterization:

2-(1-((fr,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-N-neopentylacetamide

[0311]

[0312] A solution of 2-(1-((ir,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2 -yl)sodium acetate (intermediate 4, 200 mg, 0.557 mmol), 2,2-dimethylpropan-1-amine (48.5 mg, 0.557 mmol), PyBrOP (311 mg, 0.668 mmol), DIPEA (144 mg, 1.11 mmol) and DMF (10 mL) was stirred at room temperature overnight. The mixture was quenched with 20 mL of water and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated to dryness. The residue was purified by preparative basic HPLC using a Phenomenex Synergi C ¹⁸ 250 mm X 21.2 mm column, 4 pm (eluent: 15% to 45% (v/v) CH ³ CN and 0.05% H ² O). NH ³ ) to provide the title compound (19.5 mg, 8% yield) as a white solid. MS (ESI): mass calc. for C ²³ H ³⁰ N ⁶ O, 406.25; m/z found, 407.2 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 511.84 (br s, 1H), 8.50 (s, 1H), 8.26 -8.19 (m, 1H), 7.50 - 7.45 (m, 1H), 6.74 -6.69 (m, 1H), 4.57 -4.42 (m, 1H), 4.06 (s, 2H), 2.99 - 2.92 (m , 2H), 2.59 (d, J = 6.0 Hz, 2H), 2.41-2.29 (m, 2H), 2.11-1.92 (m, 5H), 1.46- 1.30 (m, 2H), 0.88 (s, 9H).

Reference Example 45 Synthesis and Characterization:

2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-djpyrrolo[2,3-b]pyridin-2-yl)-W-^4-fluorobenzyl)acetamide

[0313]

[0314] To a solution of 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-djpyrrolo[2,3-b]pyridin-2-yl )sodium acetate (intermediate 4, 100 mg, 0.278 mmol) and (4-fluorophenyl)methanamine (90 mg, 0.56 mmol) in DMF (1 mL) were added PyBOP (217 mg, 0.417 mmol) and DIPEA (0.192 mL, 1.11 mmol) and stirred at room temperature for 87 h. The reaction was concentrated to dryness and the residue was purified by flash column chromatography (12 g silica gel column, 30-100% EtOAc in heptanes, then 10% MeOH in DCM) and by reverse phase acidic HPLC. using a Varian Pursuit XRs5 Diphenyl 100 X 30 mm column (eluent: 10-90% CH ³ CN in H ² O, 0.1 % TFA) to give the title compound as the TFA salt. This material was dissolved in 10% MeOH/CH ² Cl ² and loaded onto a 500 mg SILICYCLE SPE-R66030B-03P carbonate column (SiliaBond Acid Scavenger Solid Phase Extraction cartridge) to remove TFA and provide the title compound (43 mg, 35% yield) as a white solid. MS (ESI): mass calc. for C 25 H ²⁵ FN ⁶ O, 444.2 m/z found, 445.2 [M+H]+. 1H NMR (400 ^mHz , CDCb) 5 = 11.70 (br s, 1H), 8.58 (br ^s , 1H), 8.33 (br s, 1H), 7.47 (br s, 1H ), 7.20 (t, J =6.6 Hz, 2H), 6.98 -6.87 (m, 2H), 6.78 -6.71 (m, 1H), 4.71 (br s , 1H), 4.42 (d, J =5.6 Hz, 2H), 4.11 (br s, 2H), 2.68 - 2.47 (m, 2H), 2.43 (d, J =6.1 Hz, 2H), 2.25-1.82 (m, 5H), 1.58-1.40 (m, 2H).

Reference Example 46 Synthesis and Characterization:

Phenyl ((1 -((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(jpyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate

[0315]

[0316] A solution consisting of 2-((7r,4r)-4-(2-(aminomethyl)imidazo[4,5-a(jpyrrolo[2,3-b]pyridine-1(6^/)- yl)cyclohexyl)acetonitrile (Intermediate 5, 300 mg, 0.870 mmol), triethylamine (440 mg, 4.35 mmol), phenylcarbonochloridate (136 mg, 0.870 mmol), and CH ² Cl ² (6 mL) were stirred at 10 °C for 0.5 hr The reaction mixture was diluted with CH ² Cl ² (10 mL), washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness The residue was purified by preparative HPLC using a 150 mm X 30 mm Boston Green ODS column, 5 pm (eluent: 20% to 50% (v/v) CH ³ CN and H ² O with 10 mM NH ⁴ HCO ³ ) to give the title compound (52 mg, 14% yield) as a white solid. MS (ESI): mass calc. for C ²⁴ H ²⁴ N ⁶ O ² , 428.2; m/z found, 429.2 [M+H]+. 1H NMR (400 MHz, DMSO-cfe): 511.90 (s, 1H), 8.56 (s, 1H), 8.49 (t, J = 5.6 Hz, 1H), 7.48 (t , J = 2.8 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.25 - 7.18 (m, 1H), 7.11 (d, J = 7.6 Hz, 2H), 6.76 -6.70 (m, 1H), 4.70 (d, J = 6.0 Hz, 2H)), 4.64 -4.51 (m, 1H), 2.59 ( d, J = 6.4 Hz, 2H), 2.43-2.31 (m, 2H), 2.06-1.92 (m, 5H), 1.48-1.33 (m, 2H) .

Example 47 Synthesis and characterization:

2-(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( '(1S,4S)-4-hydroxycyclohexyl)acetamide

[0317]

[0318] A solution of sodium 2-(1-((7r;4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)acetate (Intermediate 4, 200 mg, 0.557 mmol), (1S,4S)-4-aminocyclohexanol (64.1 mg, 0.557 mmol), PyBrOP (311 mg, 0.668 mmol), DIPEA (144 mg, 1 0.11 mmol) and DMF (10 mL) was stirred at room temperature overnight. The mixture was quenched with 20 mL of water and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated to dryness. The residue was purified by preparative basic HPLC using a 150 mm x 25 mm 5 pm DuraShell column (eluent: 11% to 41% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (29 mg, 12% yield) as a white solid. MS (ESI): mass calc. for C ²⁴ H ³⁰ N ⁶ O ² , 434.2; m/z found, 435.2 [M+H]+. 1H NMR (400 MHz, DMSO-cfe): 11.82 (br s, 1H), 8.47 (s, 1H), 8.28 -8.18 (m, 1H), 7.41-7, 46 (m, 1H), 6.71 -6.65 (m, 1H), 4.43 -4.40 (m, 1H), 3.96 - 3.54 (m, 2H), 3.70 - 3.54 (m, 2H), 2.60 -2.55 (m, 3H), 2.40 - 2.25 (m, 2H), 2.07-1.89 (m, 5H), 1 .67-1.54 (m, 4H), 1.52-1.42 (m, 4H), 1.41-1.28 (m, 2H).

Reference Example 48 Synthesis and Characterization:

N -benzyl-2-(1 -((7r,4r)-4-(cyanomethyl)cyclohex¡l)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)acetamide

[0319]

[0320] Step A: N-benzyl-2-(1 -((7r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[ 2,3-b]pyridin-2-yl)acetamide. 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)ethyl acetate (intermediate 3, 65 mg, 0.13 mmol), phenylmethanamine (133 mg, 1.24 mmol), and NH ⁴ NO ³ (26 mg, 0.33 mmol) was heated to 65 °C for 25 hrs. The mixture was purified by flash column chromatography (20-100% EtOAc in heptanes, then 10% MeOH in CH ² Cl ² ) to provide the title compound (67 mg, 92%) as a light brown solid. Ms (ESI): mass calc. for C ³¹ H ³⁰ N ⁶ O ³ S, 566.2; m/z found, 567.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 58.80 (s, 1H), 8.25-8.20 (m, 2H), 7.85 (d, J =4.0 Hz, 1H), 7.59 - 7.42 (m, 3H), 7.28 - 7.16 (m, 5H), 6.83 (d, J =4.0 Hz, 1H), 4.41 (d, J =6.1 Hz, 2H), 3.99 (s, 2H), 2.41 (d, J =6.57 Hz, 2H), 2.18 - 2.10 (m, 2H), 2.05 (s, 2H ), 1.98 (br s, 2H), 1.81 (br s, 2H), 1.51-1.38 (m, 2H).

[0321] Step B: N-benzyl-2-(1-((7r,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b ]pyridin-2-yl)acetamide. A solution of N-benzyl-2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)acetamide (75 mg, 0.13 mmol) in THF (1 mL) and MeOH (1 mL) was treated with 3N NaOH (0.10 mL, 0.30 mmol) overnight at room temperature. After removing the solvents in vacuo, the residue was purified by RF-HPLC (10-90% CH ³ CN in H ² O, 0.1 % TFA) to give the title compound as a salt from ^{tF to} . This material was dissolved in MeOH and passed through a StratoSpheres SPE PL-HCO3 MP-Resin column (a solid phase extraction deacid cartridge) to remove the TFA and provide the title compound (32 mg, 56 %) as an off-white. solid. MS (ESI): mass calc. for C ²⁵ H ²⁶ N ⁶ O, 426.2; m/z found, 427.2 [M+H]+. 1H NMR (400 MHz, CDCta) = 11.25 (br s, 1H), 8.60 (br s, 1H), 8.00 (br s, 1H), 7.48-7.41 (m, 1H), 7.30 - 7.17 (m, 5H), 6.73 (d, J = 2.0 Hz, 1H), 4.66 (br s, 1H), 4.47 (d, J = 6.1 Hz, 2H), 4.08 (s, 2H), 2.54 (br s, 2H), 2.42 (d, J =6.6 Hz, 2H), 2.21 - 2.12 (m, 2H), 2.12-1.94 (m, 1H), 1.93-1.77 (m, 2H), 1.56-1.37 (m, 2H).

Reference Example 49 Synthesis and Characterization:

2-((7r,4r)-4-(2-(2-Oxo-2-(pyrrolidin-1-yl)ethyl)imidazo[4,5-a(|pyrrolo[2,3-¿>]pyridin- 1(6H)-yl)cyclohexyl)acetonitrile

[0322]

[0323] To a solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d|pyrrolo[2,3-b]pyridin- 2-yl)acetate (130 mg, 0.362 mmol) and pyrrolidine (17 mg, 0.11 mmol) in ^{dM f} (1 mL) were added PyBOP (288 mg, 0.553 mmol) and DIPEA (0.125 mL, 0.724 mmol) and the reaction mixture was stirred at room temperature for 42 h. After removing the DMF in vacuo, the residue was purified by reverse phase HPLC to give fractions containing the title compound. These fractions were dissolved in n-BuOH. To this solution was added NaHCO3 (aq) and the organic layer was separated and the aqueous layer was extracted with n-BuOH (2x) and EtOAc (1x). The organic extracts were dried, filtered, concentrated to dryness and purified by flash column chromatography to provide the title compound (8 mg, 6% yield). MS (ESI): mass calc. for C ²² H ²⁶ N ⁶ O, 390.2; m/z found, 391.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 5 = 8.53 (s, 1H), 7.48 (d, J =3.5 Hz, 1H), 6.84 (d, J =3.5 Hz, 1H), 4.49 (br s, 1H), 4.26 -4.20 (m, 2H), 3.70 (t, J =6.6 Hz, 2H), 3.47 (t, J = 7.1 Hz, 2H), 2.65-2.48 (m, 4H), 2.16-1.88 (m, 9H), 1.56-1.42 (m, 2H).

Reference Example 50 Synthesis and Characterization:

2-((7r,4r)-4-(2-(3-Hydroxy-3-phenylpyrrolidin-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile

[0324]

[0325] Ethyl 1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -carboxylate (intermediate 6, 100 mg, 0.203 mmol) was mixed with 3-phenylpyrrolin-3-ol (166 mg, 1.01 mmol) and heated to 80°C. After 3h the reaction mixture was concentrated. The residue was dissolved in MeOH/THF/NaOH (1M) (3ml/3ml/3ml) and heated at 80 °C for 1h. The reaction was concentrated to dryness and partitioned between CH ² Cl ² and H ² O (10 mL/10 mL). The organic layer was concentrated to dryness and purified by flash column chromatography (10% MeOH in CH ² Cl ² ) to provide the title compound (12 mg, 12% yield). MS (ESI): mass calc. for C ²⁷ H ²⁸ N ⁶ O ² , 468.2; m/z found, 469.3 [M+H]+. 1H NMR (500 MHz, CDCh): 12.82 - 12.41 (m, 1H), 8.74 (d, J = 1.3 Hz, 1H), 7.73 - 7.32 (m, 6H ), 6.98 -6.68 (m, 1H), 5.18 -4.89 (m, 1H), 4.46 - 3.77 (m, 4H), 2.59-1.89 (m , 12H), 1.59-1.40 (m, 2H).

Reference Example 51 Synthesis and Characterization:

2-((1r,4r)-4-(2-(2-Aminopyrimidin-5-yl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-/'/) cyclohexyl)acetonitrile

[0326]

[0327] A solution of 2-((7r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl) acetonitrile (intermediate 1, 220 mg, 0.501 mmol), 2-aminopyrimidine-5-carbaldehyde (185 mg, 1.50 mmol), sodium dithionite (261 mg, 1.50 mmol), DMSO (2.5 mL) and water (0.15 ml) was heated at 100 °C for 3 hours. Water (20ml) was added which caused a precipitate to form and filtered to collect the precipitate. The precipitate was recrystallized from 10% acetone/CH ² Cl ² to give a crude product (200 mg). This material was dissolved in MeOH/THF/NaOH (1M) (3ml/3ml/3ml) and heated at 80°C for 1h. The reaction was concentrated to dryness and partitioned between CH ² Cl ² and H ² O (10 mL/10 mL). The organic layer was concentrated to dryness and purified by flash column chromatography to provide the title compound (40 mg, 21% yield). MS (ESI): mass calc. for C ²⁰ H ²⁰ N ⁸ , 372.2; m/z found, 373.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 11.96 (s, 1H), 8.80-8.38 (m, 3H), 7.52 (d, J =3.4 Hz, 1H), 7.26 - 7.04 (m, 2H), 6.77 (d, J = 3.4 Hz, 1H), 4.54 -4.15 (m, 1H), 2.63 - 2.35 ( m, 4H), 2.24-1.85 (m, 5H), 1.52-1.24 (m, 2H).

Example 52 Synthesis and characterization:

2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1 s,3r,5R,7S)-3-hydroxyadamantan-1 -yl)acetamide

[0328]

[0329] A solution of 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2- yl)acetate (intermediate 4, 200 mg, 0.557 mmol), (1S,3R,5R,7S)-3-aminoadamantan-1-ol hydrochloride (113 mg, 0.557 mmol), DIPEA (144 mg, 1.11 mmol ) and DMF (5 mL) was stirred at 0 °C for 1 h. PyBrOP (311 mg, 0.668 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 10 mL of water and purified by preparative basic HPLC using a Kromasil 150 mm x 25 mm, 10 µm column (eluent: water (0.05% v/v ammonium hydroxide)-22% ACN 32%, v/v) to provide the title compound (30.1 mg, 11% yield) as a white solid. MS (ESI): mass calc. for C ²⁸ H ³⁴ N ⁶ O ² , 486.3; m/z found, 487.3 [M+H]+.

1H NMR (400 MHz, DMSO-ds): 11.84 (br s, 1H), 8.49 (s, 1H), 7.93 (br s, 1H), 7.47-7.44 (m , 1H), 6.72 -6.68 (m, 1H), 4.51 (s, 1H), 4.49 -4.39 (m, 1H), 3.93 (br s, 2H), 2 .61 (d, J = 5.6 Hz, 2H), 2.41-2.28 (m, 2H), 2.12 (br s, 2H), 2.05-1.92 (m, 5H) , 1.89-1.77 (m, 6H), 1.58-1.34 (m, 8H).

Reference Example 53 Synthesis and Characterization:

2-((7r,4r)-4-(2-(2-Aminopyrimidin-4-yl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-/'/) cyclohexyl)acetonitrile

[0330]

[0331] Step A: 2-((ir,4r,)-4-(2-(2-(Methylthio)pyrimidin-4-yl)imidazo[4,5-a(|pyrrolo[2,3-b] pyridin-1(6H)-yl)cyclohexyl)acetonitrile A solution of 2-((7r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b] pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1.400 mg, 1.00 mmol), 2-(methylthio)pyrimidine-4-carbaldehyde (463 mg, 3.00 mmol), sodium dithionite (523 mg, 3 00 mmol), DMSO (2.5 mL) and water (0.15 mL) was heated at 100 °C for 3 hours Water (20 mL) was added which caused a precipitate to form and was filtered to collect the precipitate.The precipitate was recrystallized from 10% acetone/CH ² Cl ² to give a crude product (200mg).This material was dissolved in MeOH/THF/NaOH (1M) (3ml/3ml/3ml ) and heated at 80 °C for 1 h. The reaction was concentrated to dryness and partitioned between CH ² Cl ² and H ² O (10 mL/10 mL). The organic layer was concentrated to dryness and purified by chromatography in flash column to give the title compound (40 mg, 21 % yield). MS (ESI): mass calc. for C ²¹ H ²¹ N ⁷ S, 403.2; m/z found, 404.2 [M+H]+.

[0332] Step B: 2-(( 7r,4rJ-4-(2-(2-Aminopyr'imidin-4-yl)imidazo[4,5-a^pyrrolo[2,3-b|pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile A solution of 2-((1r,4r)-4-(2-(2-(methylthio)pyrimidin-4-yl)imidazo[4,5-a(|pyrrolo[2 ,3-b]pyridin-1(6Hj-yl)cyclohexyl)acetonitrile (100 mg, 0.248 mmol) and 3-chlorobenzoperoxoic acid (85.5 mg, 0.496 mmol) in THF (10 mL) was stirred for 3 h. NH ⁴ OH (5M, 2 mL) was then added and the reaction mixture was heated at 100 C for 1 h.The reaction was concentrated to dryness and partitioned between CH ² Cl/H ² O (5 mL/ 5 mL).The organic layer was concentrated to dryness and the residue was purified by flash column chromatography (10% MeOH in CH ² Cl ² ) to give the title compound (10 mg, 11% yield).MS ( ESI): mass calcd for C ²⁰ H ²⁰ N ⁸ , 372.2, m/z found, 373.2 [M+H]+ 1H NMR (400 MHz, CD ³ OD): 58.67 (s, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.52 (d, J = 3.5 Hz, 1H), 7.32 (d, J = 5.1 Hz, 1H) , 6.90 (d, J = 3.5 Hz, 1H), 5.57 - 5.38 ( m, 1H), 2.77 - 2.58 (m, 2H), 2.53 (d, J = 6.3 Hz, 2H), 2.22 - 2.04 (m, 5H), 1.59 -1.39 (m, 2H).

Reference Example 54 Synthesis and Characterization:

4-(2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin-2-yl) acetamido)bicyclo[2,2,1]heptane-1-carboxamide

[0333]

[0334] To a solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl) (Intermediate 4, 200 mg, 0.557 mmol), 4-aminobicyclo[2.2.1]heptane-1-carboxamide hydrochloride (106 mg, 0.557 mmol) and DIPEA (0.291 mL, 1.67 mmol) into d dry Mf (5 mL) was added PyBrOP (285 mg, 0.612 mmol) at 0 °C. The reaction was stirred at room temperature for 4h. The mixture was quenched with 10 ml of water and extracted with EtOAc (3 x 20 ml). Both the organic and aqueous phases were concentrated to provide the sludge residue which was purified by preparative basic HPLC using a Waters Xbridge Prep OBD C ¹⁸ 150 X 30 mm X 5 pm column (eluent: 14% to 44% (v/v). ) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (36.3 mg, 13% yield) as a yellow solid. MS (ESI): mass calc. for C ²⁶ H ³¹ N ⁷ O ² , 473.3; m/z found, 474.2 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 11.83 (br s, 1H), 8.53-8.46 (m, 2H), 7.48-7.44 (m, 1H), 7, 07 (br s, 1H), 6.79 (br s, 1H), 6.70 (br s, 1H), 4.45 (br s, 1H), 3.96 (s, 2H), 2.62 - 2.57 (m, 2H), 2.40 - 2.28 (m, 2H), 2.09-1.91 (m, 5H), 1.91 -1.74 (m, 6H), 1 .73-1.61 (m, 2H), 1.61 -1.51 (m, 2H), 1.45-1.32 (m, 2H).

Example 55 Synthesis and characterization:

W-(4-(Cyanomethyl)bicyclo[2,2,1]heptane-1-yl)-2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)acetamide

[0335]

[0336] Step A: Dimethyl cyclopentane-1,3-dicarboxylate. A solution of cyclopentane-1,3-dicarboxylic acid (70.0 g, 443 mmol) and anhydrous methanol (300 mL) was cooled to 0 °C in an ice-water bath. Concentrated sulfuric acid (14 mL) was added dropwise, keeping the temperature < 15 °C. After the addition, the reaction was warmed to 90 °C and stirred overnight. The reaction was cooled to room temperature and concentrated to dryness. The residue was treated with MTBE (500 ml) and H ² O (100 ml). The aqueous layer was separated and extracted with MTBE (2 x 100 ml). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 100 mL), brine (100 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness to provide the title compound (72.5 g, 88 %) as a pale liquid. yellow oil 1H NMR (400 MHz, CDCla) 53.65 (s, 6H), 2.84-2.72 (m, 2H), 2.26-2.17 (m, 1H), 2.11-2 .02 (m, 1H), 1.96-1.88 (m, 4H).

[0337] Step B: Dimethyl bicyclo[2,2,1]heptane-1,4-dicarboxylate. To a solution of diisopropylamine (152 mL, 1090 mmol) and anhydrous THF (1000 mL) was slowly added n-Butyllithium (2.5 M in hexane, 419.0 mL, 1048 mmol) at -78 °C (dry ice/ acetone) under N ² atmosphere. The reaction was then stirred for 0.5 hours at 0 °C before being cooled to -78 °C. DMPU (404 mL, 3350 mmol) was added via addition funnel. Next, a solution of dimethyl cyclopentane-1,3-dicarboxylate (78.0 g, 419 mmol) and anhydrous THF (300 mL) were added slowly via addition funnel. The reaction was warmed to 0 °C and stirred for 30 min, then cooled to -78 °C and treated with 1-bromo-2-chloroethane solution (59.0 mL, 712 mmol) and anhydrous THF ( 200 ml). The reaction was allowed to slowly warm to room temperature and stirred for 12 hours at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (400 mL). The reaction was diluted with ethyl acetate (500ml), the organic layer separated and the aqueous layer further extracted with ethyl acetate (2 x 500ml). The combined organic extracts were washed with brine (2 x 300 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was filtered through a pad of silica gel and washed with ethyl acetate (2000ml). The filtrate was concentrated to dryness and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 30:1 to 20:1, gradient elution) to give the title compound (48.5 g, 54 ) as a white solid. 1H NMR (400 MHz, CDCl3): 3.69 (s, 6H), 2.08-1.99 (m, 4H), 1.91 (s, 2H), 1.73-1.63 (m , 4H).

[0338] Step C: 4-(Methoxycarbonyl)bicyclo[2,2,1]heptane-1-carboxylic acid. A methanol solution (80 mL) of sodium hydroxide (5.145 g, 128.6 mmol) was slowly added to a solution of dimethyl bicyclo[2,2,1]heptane-1,4-dicarboxylate (27.3 g , 129 mmol) and THF (700 mL) at 0 °C and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to dryness and the residue was triturated with MTBE (15 mL). The precipitate was collected by filtration, washed with MTBE (5 mL) and dissolved in 100 mL H ² O. The solution was acidified to pH=4 with HCbM. The precipitate was collected by filtration and dried in vacuo to provide the title compound (13.0 g, 51.0%) as a white solid. The filtrate was extracted with ethyl acetate (3 x 75 mL) and the combined organic extracts washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness to provide a second fraction of the title compound. (8.0 g, 31%) as a white solid. 1H NMR (400 MHz, DMSO-afe) 512.21 (br s, 1H), 3.59 (s, 3H), 1.94-1.86 (m, 4H), 1.74 (s, 2H) , 1.61 -1.54 (m, 4H).

[0339] Step D: Methyl 4-(((benzyloxy)carbonyl)amino)bicyclo[2,2,1]heptane-1-carboxylate. Diphenylphosphorylazide (17.1 mL, 78.6 mmol) was added to a solution of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (13.0 g, 65.6 mmol), DIPEA (22.8 mL, 131 mmol) and anhydrous toluene (200 mL) and the reaction mixture was stirred at 110 °C for 2 hours. The reaction was cooled to 50 °C and benzyl alcohol (13.6 mL, 131 mmol) added and the reaction mixture stirred at 110 °C overnight. The reaction was concentrated to dryness, dissolved in MTBE (250 mL) and washed with H ² O (150 mL). The organic layer was separated and the aqueous layer was extracted with MTBE (2 x 100 ml). The combined organic extracts were washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 10:1 to 5:1, gradient elution) to give impure product (28.5 g) as a pale yellow oil. The product was further purified by preparative acid HPLC using a Phenomenex Synergi Max-RP 250 X 50 mm X 10 pm column (eluent: 38% to 68% (v/v) CH ³ CN and H ² O with 0.1 % TFA ). The pure fractions were combined and the volatiles were removed in vacuo. The residue was diluted with H ² O (80 mL), the pH of the solution adjusted to pH = 8 with saturated aqueous NaHCO3 solution, and the resulting solution was extracted with CH ² Cl ² (3 x 100 mL). The combined organic extracts were washed with brine (75 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness to provide the title compound (17.3 g, 85%) as a colorless oil. MS (ESI): mass calc. for C ¹⁷ H ²¹ NO ⁴ , 303.2; m/z found, 303.9 [M+H]+. 1H NMR (400 MHz, DMSO-afe) 57.56 (br s, 1H), 7.37-7.30 (m, 5H), 4.97 (s, 2H), 3.58 (s, 3H) , 1.90-1.80 (m, 6H), 1.65-1.59 (m, 4H).

[0340] Step E: Methyl 4-((fert-butoxycarbonyl)aminol)bicyclo[2,2,1]heptane-1-carboxylate. A mixture of methyl 4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (17 g, 56 mmol), di-ferc-butyl dicarbonate (18.35 g, 84.06 mmol), MeOH (200 mL), and wet Pd/C (4 g, 10 wt%, 50% H ² O) was added to a 500 mL round bottom flask with a balloon of hydrogen (13 psi ) and stirred at room temperature for 72 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 20:1 to 1:1, gradient elution) to give the title compound (12.0 g, 79.5%) as a solid. white. 1H NMR (400 MHz, DMSO-dfe) 57.04 (br s, 1H), 3.57 (s, 3H), 1.93-1.78 (m, 4H), 1.77 (s, 2H) , 1.63-1.53 (m, 4H), 1.35 (s, 9H).

[0341] Step F: 4-((fert-butoxycarbonyl)amino)bicyclo[2,2,1]heptane-1-carboxylic acid. To a solution of methyl 4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (5.0 g, 19 mmol), THF (40 mL), and MeOH (20 mL) was added added aqueous sodium hydroxide (1.0 mL). M, 46.4 mL, 46.4 mmol) at room temperature and the reaction mixture was stirred at room temperature for 24 hours. The reaction was concentrated to dryness and the residue was diluted with H ² O (20 mL), acidified to pH = 4-5 with HCbM to provide a precipitate. The precipitate was dissolved in 150 mL of ethyl acetate, washed with brine (45 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (4.74 g, 100% yield). ) as a white solid. which was used directly in the next step. 1H NMR (400 MHz, DMSO-ds) 512.06 (br s, 1H), 7.00 (br s, 1H), 1.87-1.73 (m, 6H), 1.58-1.50 (m, 4H), 1.35 (s, 9H).

[0342] Step G: tert-butyl (4-(hydroxymethyl)bicyclo[2,2,1]heptan-1-yl)carbamate. A solution of borane-tetrahydrofuran complex (1.0 M, 37.1 mL, 37.1 mmol) was slowly added to a solution of 4- (( ferc- butoxycarbonyl)amino)bicyclo[2,2,1] acid heptane-1-carboxylic acid (4.74 g, 18.6 mmol) and anhydrous THF (50 mL) at 0 °C under nitrogen. After the addition was complete, the reaction was stirred at room temperature overnight. Water (30 ml) was slowly added to the mixture and stirred for a further 30 minutes. The reaction was concentrated to dryness and the residue was diluted with ethyl acetate (50 mL), washed with ^H2O (15 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. . The residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 2:1) to provide the title compound (4.0 g, 89% yield) as a white solid. TLC (petroleum ether/ethyl acetate, 2:1), Rf = 0.5. 1H NMR (400 MHz, DMSO-afej: 6.88 (br s, 1H), 4.38 (t, J = 5.4 Hz, 1H), 3.36 ( d, J = 5.4 Hz, 2H ), 1.73 (br s, 2H), 1.64-1.49 (m, 4H), 1.42 (s, 2H), 1.39-1.33 (m, 9H), 1.25 -1.16 (m, 2H).

[0343] Step H: (4-((ferc-butoxycarbonyl)amino)bicyclo[2,2,1]heptan-1-yl)methyl methanesulfonate. Pyridine (2.7 mL, 33 mmol) was added to a solution of tert-butyl (4-(hydroxymethyl)bicyclo[2.2.1]heptan-1-yl)carbamate (2.0 g, 8.3 mmol) and anhydrous CH ² Cl ² (30ml). The reaction was cooled to 0 °C and methanesulfonyl chloride (2.0 mL, 25.0 mmol) was added and the mixture stirred for 3 hours at room temperature. The reaction was diluted with CH ² Cl ² (50 ml) and water (30 ml). The organic layer was separated, washed with brine (15 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 5:1 to 1:1, gradient elution) to provide the title compound (2.58 g, 97%) as a white solid. TLC (petroleum ether/ethyl acetate, 1:1), Rf = 0.85. 1H NMR (400MHz, CDCl) 4.73 (br s, 1H), 4.21 (s, 2H), 2.98 (s, 3H), 1.93-1.90 (m, 2H), 1 .78-1.62 (m, 6H), 1.53 1.34 (m, 11H).

[0344] Step I: Fert-butyl (4-(cyanomethyl)bicyclo[2,2,1]heptan-1-yl)carbamate. To a solution of (4-((ferc-butoxycarbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methyl methanesulfonate (2.58 g, 8.07 mmol) and DMSO (25 mL) is added added sodium cyanide (1.20 g, 24.5 mmol). The reaction was heated to 100 °C and stirred for 24 hours. The reaction was diluted with 50 ml of water and extracted with ethyl acetate (3 x 40 ml). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na ² SO ⁴ , filtered, and concentrated to dryness. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 5:1) to provide the title compound (1.8 g, 89% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): 57.00 (br s, 1H), 2.67 (s, 2H), 1.82 (br s, 2H), 1.69-1.52 (m, 6H), 1.47-1.40 (m, 2H), 1.37 (s, 9H).

[0345] Step J: 2-(4-aminobicyclo[2.2.1]heptan-1-yl)acetonitrile hydrochloride. To a suspension of ferc-butyl (4-(cyanomethyl)bicyclo[2,2,1]heptan-1-yl)carbamate (850 mg, 3.40 mmol) and ethyl acetate (2 mL) at 0 °C a solution of HCl in ethyl acetate (4.0 M, 10 mL, 40 mmol) was added. After stirring at room temperature for 2 hours, the mixture was concentrated to dryness under reduced pressure. The residue was triturated with MTBE (5 ml) and the suspension isolated by filtration. The filter cake was washed with MTBE (1 mL) and dried under reduced pressure to give the title compound (450 mg, 71%) as a white solid. MS (ESI): mass calc. for C ⁹ H ¹⁴ N ² 150.12 m/z, 151.1 [M+H]+ was found.

1H NMR (400 MHz, DMSO-da) 58.59 (br.s., 3H), 2.78 (s, 2H), 1.90-1.77 (m, 2H), 1.74-1, 62 (m, 4H), 1.60 (s, 2H), 1.56 1.46 (m, 2H).

[0346] Step K: W-(4-(cyanomethyl)bicyclo[2,2,1]heptan-1 -yl)-2-(1 -((7r,4r,)-4-(cyanomethyl)cyclohexyl)- 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide. to a sodium solution 2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5a]pyrrolo[2,3-b]pyridin-2-yl)acetate (intermediate 4, 300 mg, 0.835 mmol), 2-(4-aminobicyclo[2.2.1]heptan-1-yl)acetonitrile hydrochloride (138 mg, 0.918 mmol) and DIPEA (0.291 mL, 1.67 mmol) in dry DMF (6 mL) PyBrOP (428 mg, 0.918 mmol) at 0 °C The reaction was stirred at room temperature for 12 h The mixture was quenched with 10 mL of water and extracted with EtOAc (3 x 20 mL). The combined mixtures were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness.The residue was purified by preparative HPLC using an Xtimate C18150325 mm X 5 gm column (eluent: 23% to 33% (v/v) CH ³ CN and H ² O with 10 mM NH ⁴ HCO ³ ) and by preparative TLC (dichloromethane:methanol = 15:1) to give the title compound (36.6 mg, 9% yield) as a white solid MS. (ESI): mass calcd for C ²⁷ H ³¹ N ⁷ O, 469.3, m/z found, 470.2 [M+H]+ 1H NMR (400 MHz, CD ³ OD): 5 8.53 (s, 1H), 7.48 (d, J = 4.0 Hz, 1H), 6.84 (d, J = 4.0 Hz, 1H), 4.47 (br s, 1H) , 4.07 - 4.02 (m, 2H), 2.63 (s, 2H), 2.61 - 2.50 (m, 4H), 2.18-1.98 (m, 7H), 1 .94-1.84 (m, 2H), 1.82 (s, 2H), 1.79-1.68 (m, 2H), 1.62-1.43 (m, 4H).

Reference Example 56 Synthesis and Characterization:

2- (( 1r,4r)-4- ( 2- ( 1 H -imidazol-2-yl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile

[0347]

[0348] Step A. 2- (( 1r,4r)-4- ( 2- ( 1H -imidazol-2-yl)-6-(phenylsulfonyl)imidazo[4,5-a|pyrrolo[2,3- b]pyridin-1( 6H)-yl )cyclohexyl)acetonitrile. To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino)cyclohexyl)acetonitrile (intermediate 1215 mg, 0.489 mmol) and imidazole-2-carboxaldehyde (123 mg, 1.25 mmol) as solids. DMSO (2.4ml), MeOH (2.4ml) and distilled water (1.2ml) were added resulting in a yellow mixture. Sodium hydrosulfite (282 mg, 1.62 mmol) was added as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100 °C for 2 h. The reaction was filtered to collect the solids, which were analyzed and shown to contain the product and a major impurity. The reaction was purified by flash column chromatography to provide the title compound (47 mg, 20% yield) as a tan solid. MS (ESI): mass calc. for C ²⁵ H ²³ N ⁷ U ² S, 485.2; m/z found, 486.2 [M+H]+.

[0349] Step B: 2-((1r,4r)-4-(2-(1H-imidazol-2-yl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H )-//)cyclohexyl)acetonitrile. The title compound was prepared using analogous conditions to those described in Example 1, Step B using 2- (( 1r,4r) -4-(2-(1H-imidazol-2-yl)-6-(phenylsulfonyl) inudazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (215 mg, 0.49 mmol) in place of 2-(1 -((1r,4r )-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-d]pyridin-2-yl)-W-(2-hydroxy- 2-methylpropyl)acetamide and the residue was purified by flash column chromatography (eluent = 0-5% 2 N NH3 in MeOH/EA, 12 CV) to give the title compound (15 mg, 45% yield). MS (ESI): mass calc. for C ¹⁹ H ¹⁹ N ⁷ , 345.2; m/z found, 346.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.20 (s, 1H), 12.00 (s, 1H), 8.65 (s, 1H), 7.53 (t, J = 3.0 Hz, 1H), 7.40 - 7.18 (m, 2H), 6.81 (dd, J = 3.6, 1.9 Hz, 1H), 6.34 (s, 1H), 2.62 (d, J = 6.2 Hz, 2H), 2.58-2.43 (m, 2H), 2.14-1.91 (m, 5H), 1.49-1.31 (m, 2H ).

Reference Example 57 Synthesis and Characterization:

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1 ^-dihydroimidazo^^-adpyrrolo^^-folpyridin^-iO-W-^^^-trifluoroethylOacetamide

[0350]

[0351] PyBrOP (311 mg, 0.670 mmol) was added to a 0 °C solution (ice/water) consisting of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1, Sodium 6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 4, 200 mg, 0.560 mmol), 2,2,2-trifluoroethylamine (55 mg, 0.56 mmol), W,W-diisopropylethylamine (144 mg, 1.11 mmol), and dimethylformamide (10 mL).The mixture was stirred overnight with gradual warming to room temperature before quenching with H ² O (10 mL ) and extract with ethyl acetate (20 mL X 3).The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure, purified by preparative HPLC using a 150 mm x 25 mm DuraShell column. , 5 pm (eluent: 20 to 50% (v/v) CH ³ CN and H ² O with 0.05% NH ³ to obtain pure product. The product was lyophilized to dryness to give the title compound ( 14 mg, 6%) as a white solid LCMS (ESI): RT = 3.55 min, mass calculated for C ²⁰ H ²¹ F ³ N ⁶ O: 418.17 m/z, found 419.1 [M+H]+. Reversed-phase analytical LC-MS was performed using a Phenomenex Luna-C ¹⁸ , 5032 mm X 5 pm column with a flow rate of 0.8 mL/min, eluting with a 0% to 85% acetonitrile gradient that it contained 0.05% TFA (solvent B) and water with 0.1% TFA (solvent A). The eluent composition was held at 100% A for 1 minute, followed by increasing to 60% B over the course of 4 minutes. The eluent was further increased to 85% B over the course of 2.5 minutes before returning to 100% A over the course of 2 minutes. The total execution time was 10 minutes. 1H NMR (400 MHz, DMSO-afe) 511.86 (br s, 1H), 9.03 - 8.95 (m, 1H), 8.51 (s, 1H), 7.50 - 7.46 ( m, 1H), 6.75 - 6.69 (m, 1H), 4.53 -4.39 (m, 1H), 4.12 (s, 2H), 4.04 - 3.92 (m, 2H), 2.59 (d, J = 6.0 Hz, 2H), 2.43-2.26 (m, 2H), 2.11-1.91 (m, 5H), 1.48-1 .30 (m, 2H).

Reference Example 58 Synthesis and Characterization:

4-(2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)acetamido )bicyclo[2,2,2]octane-1-carboxamide

[0352]

[0353] Step A: tert-butyl (4-(chlorocarbonyl)bicyclo[2,2,2]octan-1-yl)carbamate. Oxalyl chloride (0.61 mL, 7.2 mmol) was added slowly to a solution of 4-((fert-butoxycarbonyl)amino)bicyclo[2,2,2]octane-1-carboxylic acid (1.3 g , 4.8 mol) and anhydrous CH ² Cl ² (30 mL) at 0 °C. Next, 4 drops of DMF were added and the reaction was stirred for 1.5 hours at 0 °C. The reaction was concentrated to dryness under reduced pressure to provide the title compound (1.36 g, 98% yield) as a white solid, which was used in the next step without further purification. Step B: Fert-butyl (4-carbamoylbicyclo[2,2,2]octan-1-yl)carbamate. tert-Butyl (4-(chlorocarbonyl)bicyclo[2.2.2]octan-1-yl)carbamate (1.36 g, 4.73 mmol) and anhydrous CH ² Cl ² (40 mL) were added to a 100 mL three-necked flask and cooled to 0 °C (ice/water). Ammonia gas was bubbled through the reaction for 25 minutes and stirred for 5 minutes at room temperature before diluting with water (20 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (15 mL X 2). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to provide the title compound (260 mg, 20% yield), which was used without further purification. 1H Rm N (400 mHz, DMSO-afe) 56.89 (br. s., 1H), 6.66 (br. s., 1H), 6.36 (br. s., 1H), 1, 73-1.59 (m, 12H), 1.32 (s, 9H).

[0354] Step C: 4-aminobicyclo[2,2,2]octane-1-carboxamide hydrochloride. To a solution of ferc-butyl (4-carbamoylbicyclo[2,2,2]octan-1-yl)carbamate (260 mg, 0.969 mmol) in CH ² Cl ² (5 mL) was added HCl in ethyl acetate (4 M, 4 mL) at 0 °C and stirred at 0 °C for 1 hour. The reaction was concentrated to dryness, dissolved in water (5ml) and washed with ethyl acetate (5ml X 2). The aqueous phase was concentrated to dryness and lyophilized to provide the title compound (150 mg, 75% yield) as a white solid. 1H NMR (400 MHz, DMSO-afe): 58.23 (br s, 3H), 7.05 (br s, 1H), 6.82 (br s, 1H), 1.71 (br s, 12H) .

[0355] Step D: 4-(2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridine -2-yl)acetamido)bicyclo[2,2,2]octane-1-carboxamide. A solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl) acetate (intermediate 4, 200 mg, 0.557 mmol), 4-aminobicyclo[2.2.2]octane-1-carboxamide hydrochloride (114 mg, 0.557 mmol) and DIPEA (0.291 mL, 1.67 mmol) in dry DMF (5 mL) PyBrOP (285 mg, 0.612 mmol) was added at 0 °C. The reaction was stirred at room temperature for 15h. The mixture is quenched with 10 mL of water and extracted with EtOAc (3 x 20 mL). Both the organic and aqueous phases were concentrated and the resulting residue was purified by basic preparative HPLC using a Waters Xbridge Prep OBD Cis 150 X 30 mm X 5 gm column (eluent: 14% to 44% (v/v) MeOH and H ² O with 0.05% NH ³ ) to provide the title compound (39.5 mg, 14% yield) as a yellow solid. MS (ESI): mass calc. for C ²⁷ H ³³ N ⁷ O ² , 487.3; m/z found, 488.2 [M+H]+. 1H NMR (400 MHz, DMSO-cfe): 11.83 (br s, 1H), 8.48 (s, 1H), 7.90 (br s, 1H), 7.48-7.44 (m , 1H), 6.94 (br s, 1H), 6.74 -6.67 (m, 2H), 4.41 (br s, 1H), 3.92 (s, 2H), 2.63 - 2.57 (m, 2H), 2.39 - 2.28 (m, 2H), 2.08-1.91 (m, 5H), 1.90-1.78 (m, 6H), 1, 78-1.66 (m, 6H), 1.44-1.32 (m, 2H).

Example 59 Synthesis and characterization:

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-W-( 3-hydroxy-3-methylbutyl)acetamide

[0356]

[0357] A solution of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2- Sodium yl)acetate (Intermediate 4, 200 mg, 0.557 mmol), 4-amino-2-methylbutan-2-ol (57.4 mg, 0.557 mmol), PyBrOP (311 mg, 0.668 mmol), DIPEA (144 mg , 1.11 mmol) and DMF (10 mL) was stirred at room temperature overnight. The mixture was quenched with 20 mL of water and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous MgSO ⁴ and concentrated to dryness. The residue was purified by preparative basic HPLC using a 150 mm x 25 mm, 5 gm DuraShell column (eluent: 8% to 38% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (15.2 mg, 6% yield) as a white solid. MS (ESI): mass calc. for C ²³ H ³⁰ N ⁶ O ² , 422.2; m/z found, 423.2 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 511.55 (br s, 1H), 8.50 (s, 1H), 8.01-7.53 (m, 1H), 7.47-7.41 (m, 1H), 6.76 -6.71 (m, 1H), 4.59 -4.48 (m, 1H), 4.05 - 3.97 (m, 1H), 3.98 (br s, 2H), 3.27 - 3.18 (m, 2H), 2.59 -2.56 (m, 2H), 2.42 - 2.32 (m, 2H), 2.08-1, 97 (m, 5H), 1.65-1.57 (m, 2H), 1.51-1.37 (m, 2H), 1.16-1.10 (m, 6H).

Reference Example 60 Synthesis and Characterization:

2- (( 1r,4r)-4- ( 2- ( 1H -Pyrazol-3-yl)imidazo[4,5-a]pyrrolo[2,3-¿>]pyridin-1(6H)-yl) cyclohexyl)acetonitrile

[0358]

[0359] Step A: 2-(( 1r,4r)-4-(6-(phenylsulfonyl)-2-(1H-pyrazol-3-yl)imidazo[4,5-a]pyrrolo[2,3- b]pyridin-1( 6H)-yl )cyclohexyl)acetonitrile. To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino)cyclohexyl)acetonitrile (Intermediate 1, 150 mg, 0.341 mmol) and 1 H-pyrazole-3-carbaldehyde (54 mg, 0.56 mmol) as solids. DMSO (1.7ml), MeOH (1.7ml) and distilled water (0.9ml) were added resulting in a yellow mixture. Sodium hydrosulfite (134 mg, 0.770 mmol) was added as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100 °C and heated for 3 h. The vial was cooled to room temperature and the reaction was added to 50 mL of water with stirring. A brown solid formed and was collected by filtration and dried overnight. The residue was purified by flash column chromatography to provide the title compound (84 mg, 51 % yield). MS (ESI): mass calc. for C ²⁵ H ²³ N ⁷ O ² S, 485.57; m/z found, 485.9 [M+H]+.

[0360] Step B: 2-(( 1r,4r)-4-(2-(1H-pyrazol-3-yl)inudazo[4,5-a]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile. The title compound was prepared using analogous conditions to those described in Example 1, Step B using 2- (( 1r,4r) -4-(6-(phenylsulfonyl)-2-(1H-pyrazol-3-yl) imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (84 mg, 0.17 mmol) in place of 2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-adpyrrolo[2,3-a]pyridin-2-yl)-W-( '2-Hydroxy-2-methylpropyl)acetamide and the residue was purified by flash column chromatography (0-10% 2N NH3 in MeOH/DCM) to give the title compound (21 mg, 35% yield). MS (ESI): mass calc. for C ¹⁹ H ¹⁹ N ⁷ , 345.4; m/z found, 345.9 [M+H]+. 1H NMR (500 MHz, CD ³ OD): 58.61 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 3.5 Hz, 1H ), 6.94 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 3.5 Hz, 1H), 5.78 - 5.42 (m, 1H), 2.72 - 2.59 (m, 2H), 2.53 (d, J = 6.0 Hz, 2H), 2.19-1.97 (m, 5H), 1.55-1.37 (m, 2H ).

Reference Example 61 Synthesis and Characterization:

EZ)-N- (( 1- (( 1r,4r)-4- ( cyanomethyl)cyclohexyl)-1 ,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxyisobutyrimidamide

[0361]

[0362] Step A: Isobutyraldehyde oxime. A mixture of isobutyraldehyde (2.00 g, 27.7 mmol), hydroxylamine hydrochloride (5.78 g, 83.2 mmol), sodium acetate (6.83 g, 83.2 mmol) was stirred at 70 °C. ), ethanol (100 ml) and water (20 ml). for 10 hrs. EtOH was removed under reduced pressure and water (20 mL) was added. The mixture was extracted with ethyl acetate (30ml X 2). The combined extracts were dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure to give the title compound as a colorless oil (2.00 g, 83% yield, contained 30% isomer). 1H NMR (400 MHz, CDCla) 57.38 (d, J = 5.6 Hz, 1H), 2.56 - 2.45 (m, 1H), 1.09 (d, J = 7.2 Hz, 6H). Isomer: 1H NMR (400 MHz, CDCla) 56.54 (d, J = 7.2 Hz, 1H), 3.27-3.16 (m, 1H), 1.07 (d, J = 6.4 Hz, 6H).

[0363] Step B: N-hydroxyisobutyrimidoyl chloride. A mixture of isobutyraldehyde oxime (2.0 g, 23 mmol), N-chlorosuccinimide (6.1 g, 46 mmol) and DMF (20 mL) was stirred for 2 h at 10 °C under N ² . Water (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The extract was dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate in petroleum ether, 0-15%) to give the title compound as a colorless oil (1.0 g, 32%). 1H NMR (400 MHz, cDcta) 57.70 (s, 1H), 2.87-2.75 (m, 1H), 1.21 (d, J=7.2 Hz, 6H).

[0364] Step C: (EZ)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3- b]pyridin-2-yl)methyl)-N'-hydroxyisobutyrmididaide A solution of 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (Intermediate 5, 200 mg, 0.580 mmol), N-hydroxyisobutyrimidoyl chloride (71 mg, 0.58 mmol), triethylamine (0.243 mL, 1.74 mmol) and DMF (5 mL) was stirred for 2 h at 10 C. The reaction was concentrated to dryness and the residue was washed with acetonitrile (5 mL) by filtration to give the title compound as a white solid (15 mg, The filtrate was purified by preparative basic HPLC using a 150 mm x 25 mm, 5 gm Gemini column (eluent: 20 to 50% (v/v) CH3CN and H ² O with 0.05% of NH3) and then by preparative acid HPLC with a Phenomenex Gemini 150 mm X 25 mm, 10 gm column (eluent: 5% to 35% (v/v) of CH3CN and aqueous HCl (0.006 N). The pure fractions of the second purification by H PLC were collected, adjusted to pH = 7-8 with saturated aqueous NaHCO ³ , and the volatiles were removed under reduced pressure. The precipitated white solid was filtered, washed with water (2 mL X 3) and lyophilized to dryness to provide a second portion of the title compound (40 mg, 17% yield). MS (ESI): mass calculated for C ²¹ H ²⁷ N ⁷ O, 393.23; m/z found, 394.1 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 511.88 (s, 1H), 9.20 (br s, 1H), 8.56 (s, 1H), 7.47 (d, J = 3.2 Hz, 1H), 6.72 (d, J = 3.2 Hz, 1H), 6.23 (t, J = 5.6 Hz, 1H), 4.74 - 4.59 (m, 3H), 2.89 - 2.80 (m, 1H), 2.60 (d, J = 6.0 Hz, 2H), 2.42 - 2.25 (m, 2H), 2.07-1.87 ( m, 5H), 1. 56 1.42 (m, 2H), 1.00 (d, J = 6.4 Hz, 6H).

Example 62 Synthesis and characterization:

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1-isobutylpiperidin-4-yl)acetamide

[0365]

[0366] A mixture of ethyl 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)acetate (intermediate 3, 300 mg, 0.59 mmol) and 1-isobutylpiperidin-4-amine (976 mg, 5.93 mmol) was heated at 125 °C in the microwave for 22 hours. The reaction was cooled to room temperature, then 1,4-dioxane (2.37ml) and 3N KOH (1.58ml) were added. The vial was heated at 80 °C for 2 h in the microwave, then purified by basic HPLC using a 50 mm X 100 mm Xbridge Prep OBD C ¹⁸ column, 5 pm (eluent = 0-100% aq. NH ⁴ OH/ ACN (10 min)) to give the title compound (111 mg, 39% yield). MS (ESI): mass calc. for C ²⁷ H ³⁷ N ⁷ O, 475.31; m/z found, 476.3 [M+H]+. 1H NMR (500 MHz, CD ³ OD): 58.54 (s, 1H), 7.49 (d, J = 3.5 Hz, 1H), 6.86 (d, J = 3.5 Hz, 1H ), 4.54 (s, 1H), 4.11 -4.04 (m, 1H), 3.75 - 3.64 (m, 1H), 2.89 (d, J = 11.8 Hz, 2H), 2.63-2.54 (m, 3H), 2.19-1.78 (m, 13H), 1.69-1.44 (m, 4H), 0.97-0.88 ( m, 7H).

Reference Example 63 Synthesis and Characterization:

2-((1r,4r)-4-(2-(2H-Tetrazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile

[0367]

[0368] Step A: 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-(2H-tetrazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )amino)cyclohexyl)acetonitrile (Intermediate 1, 200 mg, 0.455 mmol) and 2H -tetrazol-5-carbaldehyde (97 mg, 0.998 mmol) as solids. DMSO (2.2ml), MeOH (2.2ml) and distilled water (1.2ml) were added resulting in a yellow mixture. Sodium hydrosulfite (285 mg, 1.64 mmol) was added as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100 °C for 4 h. The reaction was poured into water, resulting in the formation of a precipitate, which was filtered to provide the title compound (199 mg, 89% yield) as a tan solid, which was used without further purification. MS (ESI): mass calc. for C ²³ H ²¹ N ⁹ O ² S, 487.15; m/z found, 488.2 [M+H]+.

[0369] Step B: 2-((1r,4r)-4-(2-(2H-Tetrazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H )-//)cyclohexyl)acetonitrile. The title compound was prepared using analogous conditions to those described in Example 1, Step B using 2- (( 1r,4r) -4-(6-(phenylsulfonyl)-2-(2H-tetrazol-5-yl)imidazo [4,5-d]pyrrolo[2,3-b]pyr'idin-1(6H)-yl)cyclohexyl)acetonitrile (199 mg, 0.41 mmol) in place of 2-(1-((1r, 4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-d¡h¡dro¡m¡dazo[4,5-d]p¡rrolo[2,3-d]p¡r ¡d¡n-2-¡l)-W-(2-hydroxy-2-methylpropyl)acetamide and the residue was purified by flash column chromatography (0-30% 2N NH3 in MeOH/EA to give the product compound). titer (12 mg, 8% yield) MS (ESI): mass calculated for C ¹⁷ H ¹⁷ N ⁹ , 347.16 m/z found, 348.2 [M+H]+ 1H NMR (500 MHz, CD ³ OD): 58.57 (s, 1H), 7.43 (t, J = 2.8 Hz, 1H), 6.82 (t, J = 3.0 Hz, 1H), 5.13 -4 .90 (m, 1H), 2.55-2.29 (m, 3H), 2.10-1.83 (m, 4H), 1.43-1.13 (m, 4H).

Example 64 Synthesis and characterization:

2-(1 -((1r,4r)-4-(C¡anomethyl)cyclohex¡l)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(1H-pyrazol-4-yl)acetamide

[0370]

[0371] To a solution of 2-(1-((7r,4riM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl) sodium acetate (intermediate 4, 100 mg, 0.278 mmol) and ^1H -pyrazole-4-amine (50.0 mg, 0.602 mmol) in DmF (1.2 mL) PyBrOP (217 mg, 0.417 mmol) and DIPEA (0.144 mL, 0.835 mmol) and stirred at room temperature overnight.The DMF was removed under reduced pressure and the residue was purified by flash column chromatography and reverse phase HPLC to give the product as the TFA salt. Material was dissolved in 10% MeOH/CH ² Cl ² and passed through a 500 mg carbonate column SILICYCLE SPE-R66030B-03P (SiliaBond Acid Scavenger Solid Phase Extraction cartridge) to remove TFA and provide the title compound (37.0 mg, 33% yield) as a white solid MS (ESI): mass calcd for C ²¹ H ²² N ⁸ O, 402.19, m/z found, 403.2 [M+H]+ 1H NMR (400 MHz, CD ³ OD) = 8.55 (s, 1H), 7.92 (br s, 1H), 7.65 (br s, 1H), 7.48 (d, J = 3.5 Hz, 1H), 6.83 (d, J =3.5 Hz, 1H), 4.59 (br s, 1H), 4.26 -4.20 ( m, 1H), 2.63-2.43 (m, 4H), 2.17-2.00 (m, 6H), 1.44 (q, J =11.8 Hz, 2H).

Reference Example 65 Synthesis and Characterization:

2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-W-f4,4- dimethylcyclohexyl)acetamide

[0372]

[0373] A solution of 2-(1-((7r,4riM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)acetate sodium (Intermediate 4, 800 mg, 2.23 mmol), 4,4-dimethylcyclohexanamine (283 mg, 2.23 mmol) and DIPEA (575 mg, 4.45 mmol) in dry DMF (10 mL) was shaken at 0 °C for 1 h PyBrOP (1.25 g, 2.67 mmol) was added at 0 °C and stirred at room temperature overnight The mixture was quenched with 60 mL of water and extracted with CH ² Cl ² (3 x 80 mL) The organic phases were combined and concentrated to dryness The residue was purified by preparative HPLC using a 150 mm X 25 mm DuraShell column, 5 pm (eluent: H ² O (0.05%) NH4HC03)-a Cn from 28 to 58%, v/v) and by preparative TLC (dichloromethane:methanol = 12:1) to give the title compound (135 mg, 13% yield) as a white solid MS (ESI): mass calcd for C ²⁶ H ³⁴ N ⁶ O, 446.28, m/z found, 447.3 [M+H]+ 1H NMR (400 MHz, DMSO-cfe): 5 11.83 (br s, 1H), 8.49 (s, 1H), 8.21 (d, J = 7.5 Hz, 1 H), 7.48 - 7.44 (m, 1H), 6.72 -6.69 (m, 1H), 4.48 (br s, 1H), 3.96 (s, 2H), 3, 57 - 3.45 (m, 1H), 2.60 (d, J = 5.8 Hz, 2H), 2.43 - 2.27 (m, 2H), 2.09-1.93 (m, 5H), 1.67-1.58 (m, 2H), 1.47-1.32 (m, 6H), 1.28-1.16 (m, 2H), 0.91(s, 3H) , 0.89 (s, 3H).

Reference Example 66 Synthesis and Characterization:

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-djpyrrolo[2,3-b]pyridin-2-yl)-W-^1-methylpiperidin-4 -yl)acetamide

[0374]

[0375] The title compound (45 mg, 18% yield) was prepared using analogous conditions to those described in Example 50, using 1-methylpiperidin-4-amine in place of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²⁴ H ³¹ N ⁷ O, 433.26; m/z found, 434.2 [M+H]+. 1H NMR (500 MHz, CDCla): 12.15 - 11.52 (m, 1H), 8.66 (s, 1H), 7.67 (s, 1H), 7.39 (dd, J = 3 .5, 1.9 Hz, 1H), 6.73 -6.57 (m, 1H), 4.66 (s, 1H), 3.98 (s, 2H), 3.80 - 3.60 ( m, 1H), 2.90-2.60 (m, 4H), 2.34 (d, J = 6.5 Hz, 2H), 2.22-1.96 (m, 12H), 1.84 -1.78 (m, 2H), 1.50-1.41 (m, 2H).

Reference Example 67 Synthesis and Characterization:

2-((7r;4r,)-4-(2-(2-(1,1-Dioxidothiomorpholino)-2-oxoethyl)imidazo[4,5-a(]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile

[0376]

[0377] To a solution of sodium 2-(1-((7r,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-¿> ]pyridin-2-yl)acetate (intermediate 4, 66 mg, 0.18 mmol) and thiomorpholine 1,1-dioxide (63 mg, 0.37 mmol) in DMF (2 mL) PyBOP (190 mg, 0 0.37 mmol) and DIPEA (0.1 mL, 0.58 mmol) and stirred at room temperature for 64 h.The reaction was concentrated to dryness and the residue was purified by reverse phase preparative HPLC using a Varian Pursuit XRs5 column. Diphenyl 100 X 30 mm (eluent: 10-90% CH ³ CN in H ² O, 0.1 % TFA) to give the title compound (20 mg, 19% yield) as a foam MS (ESI): mass Calcd for C ²² H ²⁶ N ⁶ O ³ S, 454.18, m/z found, 455.3 [M+H]+ 1H NMR (400 MHz, CD ³ OD) 5 = 8.84 (s, 1H), 7.75 (d, J =3.5 Hz, 1H), 7.12 (d, J =3.5 Hz, 1H), 4.62 (br s, 1H), 4.22 -4 .07 (m, 5H), 3.39 - 3.32 (m, 2H), 3.23 - 3.14 (m, 2H), 2.56 (d, J =6.1 Hz, 4H), 2.23-2.09 (m, 6H), 1.60-1.47 (m, 2H).

Example 68 Synthesis and characterization:

2-(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl)-W- (4-(hydroxymethyl)benzyl)acetamide

[0378]

[0379] To a solution of 2-(1 -((ir,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridine Sodium -2-yl)acetate (intermediate 4, 100 mg, 0.278 mmol) and (4-(aminomethyl)phenyl)methanol (76 mg, 0.56 mmol) in DMF (1 mL) were added PyBOP (217 mg, 0.417 mmol) and DIPEA (0.144 mL, 0.835 mmol) and stirred at room temperature for 87 h.After removing the DMF in vacuo, the residue was purified by flash column chromatography and reverse phase HPLC to give the compound as the TFA salt This material was dissolved in 10% MeOH in CH ² CL, loaded onto a SILICYCLE SPE-R66030B-03P carbonate 500 mg column (SiliaBond acid scavenger SPE cartridge) to remove TFA and eluted with 10% MeOH in CH ² Cl ² to give the title compound (34 mg, 27% yield) as a white solid MS (ESI): mass calcd for C ²⁶ H ²⁸ N ⁶ O ² , 456.23, m/z found, 457.2 [M+H]+, 1H NMR (400 MHz, CDCh) 5 = 11.77 (br s, 1H), 8.53 (br s, 1H), 7.84 (br s, 1H), 7.49 (t, J = 2.8 Hz, 1H), 7, 27 - 7.18 (m, 4H), 6.76 (br s, 1H), 4.92 (t, J =12.1 Hz, 1H), 4.60 (s, 2H), 4.42 ( d, J =5.1 Hz, 2H), 4.11 (s, 2H), 2.64-2.47 (m, 2H), 2.42 (d, J =6.1 Hz, 2H), 2.25 - 2.14 (m, 2H), 2.14 - 2.02 (m, 2H), 2.00-1.81 (m, 2H), 1.59-1.44 (m, 2H) ).

Reference Example 69 Synthesis and Characterization:

2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-W-t-cyclohexylmethyl)acetamide

[0380]

[0381] A solution of 2-(1-((ir,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2 -yl)sodium acetate (Intermediate 4, 1.00 g, 2.78 mmol), cyclohexylmethanamine (315 mg, 2.78 mmol), DIPEA (719 mg, 5.57 mmol), and DMF (10 mL) was stirred ) at 0 °C for 1 h. PyBrOP (1.56 g, 3.34 mmol) was then added and stirred at room temperature overnight. The mixture was quenched with 10 mL of water and purified by preparative basic HPLC using a Kromasil 150 mm x 25 mm, 10 gm column (eluent: water (0.05% v/v ammonium hydroxide)-33% ACN 43%, v/v) to provide the title compound (121 mg, 10% yield) as a white solid. MS (ESI): mass calc. for C ²⁵ H ³² N ⁶ O, 432.26; m/z found, 433.2 [M+H]+. 1H NMR (400 mHz, DMSO-afe): 11.84 (br s, 1H), 8.49 (s, 1H), 8.28 - 8.21 (m, 1H), 7.48 - 7 .44 (m, 1H), 6.73 -6.67 (m, 1H), 4.54 -4.42 (m, 1H), 3.99 (s, 2H), 2.98 - 2.91 (m, 2H), 2.58 (d, J = 6.0 Hz, 2H), 2.42-2.27 (m, 2H), 2.10-1.92 (m, 5H), 1, 74-1.56 (m, 5H), 1.46-1.29 (m, 3H), 1.25-1.06 (m, 3H), 0.95-0.82 (m, 2H).

Reference Example 70 Synthesis and Characterization:

1-((1-((ir,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin-2-yl)methyl )-3-phenylurea and its trifluoroacetate salt

[0382]

[0383] Step A: tert-butyl ((1-((ir,4r,)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[ 2,3-b]pyridin-2-yl)methyl)carbamate A solution of 2-(( 7r,4r^-4-((5-nitro-1 -(phenylsulfonyl)-1H-pyrrolo[2,3 -b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 1.0 g, 2.3 mmol), ferc -butyl (2-oxoethyl)carbamate (0.82 g, 5.2 mmol) , sodium hydrosulfite (1.2 g, 5.7 mmol) in DMSO (3 mL), methanol (10 mL) and water (5 mL) was stirred for 15 h at 100 °C in a closed vessel.The reaction was concentrated to dryness and the residue was dissolved in water and CH ² CL.The combined organic layer was washed with water and the aqueous phase was re-extracted with CH ² CL.The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to dryness The residue was purified by flash column chromatography to give the title compound (750 mg, 60% yield) as a white solid MS (ESI): mass calcd for C ²⁸ H ³² N ⁶ O ⁴ S, 548.22; m/z found, 549.3 [M+H]+.

[0384] Step B: 2-((7r,4r,M-(2-(Aminomethyl)-6-(phenylsulfonyl)imidazo[4,5-d|pyrrolo[2,3-b]pyridin-1(6Hj- yl)cyclohexyl)acetonitrile 2,2,2-trifluoroacetate A solution of ferc-butyl ((1-((7r,4rM-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydro ¡nudazo[4,5-d]p¡rrolo[2,3-b]p¡r¡d¡n-2-¡l)methyl)carbamate (72 mg, 0.13 mmol) and CH2Cl2(1 mL) was treated with TFA (0.10 mL) at room temperature for 3 h and concentrated in vacuo to dryness to provide the title compound (73 mg, 99% yield) MS (ESI): mass calcd for C ²³ H ²⁴ N ⁶ O ² S, 448.17, m/z found, 449.2 [M+H]+.

[0385] Step C: 1 -((1 -((7r,4rJ-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)methyl)-3-phenylurea A solution of 2-((7r,4r,M-(2-(aminomethyl)-6-(phenylsulfonyl)imidazo[4,5-d|pyrrolo[ 2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (73 mg, 0.13 mmol), triethylamine (0.10 mL, 0.72 mmol) and isocyanatobenzene (60 mg, 0.50 mmol ) in DMF (1.5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness to provide the free base compound, 1-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4 ,5-a]pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-phenylurea. This free base compound was purified by flash column chromatography to provide the title compound as its trifluoroacetate salt (50 mg, 68% yield). 1H NMR (400 MHz, CDCl3): 58.70 (s, 1H), 8.17 (d, J = 7.6 Hz, 2H), 8.00 (s, 1H), 7.80 (d, J = 4.0 Hz, 1H), 7.57 - 7.48 (m, 1H), 7.48 - 7.39 (m, 2H), 7.25 (d, J = 8.59 Hz, 2H) , 7.13 (t, J =7.3 Hz, 2H), 6.91 (br t, J =6.6 Hz, 1H), 6.80 (br d, J =3.5 Hz, 1H) , 6.76 (br s, 1H), 4.88 -4.76 (m, 2H), 4.62 (br s, 1H), 2.34 (br d, J =5.1 Hz, 2H) , 2.29-2.02 (m, 5H), 1.95 (br s, 2H), 1.48-1.31 (m, 2H).

[0386] Step D: 1 -((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin- 2-yl)methyl)-3-phenylurea A solution of 1 -((1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5 -a(]pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-phenylurea (50 mg, 0.088 mmol) in THF (0.8 mL) and MeOH (0.8 mL) was treated with 3 M NaOH (0.08 mL, 0.24 mmol) at room temperature for 3 h and concentrated in vacuo The residue was purified by flash column chromatography (2-10% MeOH in CH ² CL) to give the compound of the title (30 mg, 80%) as a white solid MS (ESI): mass calcd for C ²⁴ H ²⁵ N ⁷ O, 427.21, m/z found, 428.3 [M+H]+. 1H NMR (400 MHz, CDCh) = 11.91 (br s, 1h), 8.62 (s, 1H), 8.44 (br s, 1H), 7.35 (br s, 1H), 7.31 - 7.20 (m, 2H), 7.09 (br s, 2H), 6.88 (br s, 1H), 6.59 (br s, 1H), 4.87 (br s, 2H), 4 .55 (br s, 1H), 2.39 (br s, 2H), 2.25 (br s, 2H), 2.11-1.75 (m, 5H), 1.43-1.28 ( m, 2H).

Reference Example 71 Synthesis and Characterization:

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-methoxy-2-methylpropyl)acetamide

[0387]

[0388] A solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin- 2-yl)acetate (intermediate 4, 65 mg, 0.18 mmol) and 2-methoxy-2-methylpropan-1-amine (50 mg, 0.36 mmol) in DMF (2 mL) were added PyBOP (150 mg , 0.30 mmol) and DIPEA (0.10 mL, 0.58 mmol) and stirred at room temperature for 64 h.The reaction was concentrated to dryness and the residue was purified by reverse phase preparative HPLC using a Varian column. Pursuit XRs5 Diphenyl 100 X 30 mm (eluent: 10-90% CH ³ CN in H ² O, 0.1 % TFA) to give the title compound (23 mg, 24% yield) as a foam MS (ESI) : mass calcd for C ²³ H ³⁰ N ⁶ O ² , 422.24, m/z found, 423.3 [M+H]+ 1H NMR (400 MHz, CD ³ OD) 5 = 8.80 (s , 1H), 7.75 (d, J =3.0 Hz, 1H), 7.10 (d, J =3.5 Hz, 1H), 4.68 (br s, 1H), 3.35 - 3.32 (m, 3H), 3.25 (s, 3H), 2.56 (d, J =6.1 Hz, 4H), 2.29 - 2.04 (m, 6H), 1.63 -1.44 (m, 2H), 1.20 (s, 6H).

Reference Example 72 Synthesis and Characterization:

(Z*)-W-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroinudazo[4,5-a(]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)-3-methoxypropanimidamide, the structure being the (Z) or (E) isomer, and the notation (Z) and its corresponding structure below are chosen arbitrarily

[0389]

[0390] Step A: ( Z)-N'- (( 1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2yl)methoxy)-3 -methoxypropanimidamide. A solution of 2-((7r,4rM-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile (intermediate 8, 300 mg, 0.641 mmol), W-hydroxy-3-methoxypropanimidamide (227 mg, 1.92 mmol), CS ² CO ³ (1.04 g, 3.21 mmol), and DMF (5 mL) stirred for 18 h at 10 C. The reaction was concentrated to dryness to provide the title compound (1.6 g, 100% yield), which was used in the next step without further purification.MS (ESI): mass Calcd for C ²⁷ H ³¹ N ⁷ O ⁴ S, 549.22, m/z found, 550.1 [M+H]+.

[0391] Step B: (Z*)-N'-((1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-¿> ]pyridin-2-yl)methoxy)-3-methoxypropanimidamide The title compound was prepared using analogous conditions to those described in Example 1, Step B using ( Z )-N'- (( 1 -((ir,4r ,)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methoxy)-3-methoxypropanimidamide ( 1.6 g, 0.64 mmol, purity 22%) instead of 2-(1-((ir,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4 ,5-a]pyrrolo[2,3-b]pyridin-2-yl)-N-('2-hydroxy-2-methylpropyl)acetamide to give the title compound (65 mg, 24% yield), which first purified by flash column chromatography (DCM: methanol = 100:0 to 85:15), and then purified by preparative HPLC using Gemini column 150 mm x 25 mm, 5 pm (eluent: 17% to 47% (v/v) of CH ³ CN and H ² O with 0.05% NH ³ ) MS (ESI): Calcd mass for C ²¹ H ²⁷ N ⁷ O ² , 409.22, m/z found ado, 410.3 [M+H]+. MS (ESI): mass calc. for C ²¹ H ²⁷ N ⁷ O ² , 409.5; m/z found, 410.3 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 511.88 (s, 1H), 8.54 (s, 1H), 7.47 (s, 1H), 6.73 (s, 1H), 5.76 (s, 2H), 5.16 (s, 2H), 4.81 -4.66 (m, 1H), 3.45 (t, J = 6.4 Hz, 2H), 3.18 (s, 3H), 2.58 (d, J = 4.8 Hz, 2H), 2.43 - 2.27 (m, 2H), 2.17 (t, J = 6.4 Hz, 2H), 2, 10 1.89 (m, 5H), 1.49-1.33 (m, 2H).

Example 73 Synthesis and characterization:

2-(( 7r,4r^-4-(2-(2-(4-(Hydroxymethyl)piperidin-1 -yl)-2-oxoetM)imidazo[4,5-d]pyrrolo[2,3-b] pyridin-1(6Hj-yl)cyclohexyl)acetonitrile

[0392]

[0393] A solution of sodium 2-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- il)acetate (intermediate 4.65 mg, 0.18 mmol) and piperidin-4-ylmethanol (55 mg, 0.36 mmol) in DMF (2 mL) were added PyBOP (150 mg, 0.30 mmol) and DIPEA (0.10 mL, 0.58 mmol) and stirred at room temperature for 64 h The reaction was concentrated to dryness and the residue was purified by reverse phase preparative HPLC using a Varian Pursuit XRs5 Diphenyl 100 X 30 mm column ( eluent: 10-90% CH ³ CN in H ² O, 0.1 % TFA) to give the title compound (11 mg, 11 % yield) as a foam MS (ESI): mass calcd for C ²⁴ H ³⁰ N ⁶ O ² , 434.24, m/z found, 435.3 [M+H]+ 1H NMR (400MHz, CD ³ OD) 5 = 8.81 (d, J =1.5 Hz, 1H ), 7.75 (d, J =3.5 Hz, 1H), 7.13 - 7.07 (m, 1H), 4.66 - 4.48 (m, 2H), 4.32 (d, J =6.1 Hz, 1H), 4.17 (br t, J =13.4 Hz, 1H), 3.47 (d, J =5.6 Hz, 1H), 3.36 - 3.24 (m, 2H), 2.78 (dq, J =2.5, 12.6 Hz, 1H), 2.56 (d, J =5.6 Hz, 4H), 2.25-2.0 8 (m, 6H), 1.99-1.77 (m, 3H), 1.61-1.14 (m, 4H).

Example 74 Synthesis and characterization:

2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-('1H -pyrazol-3-yl)acetamide

[0394]

[0395] Step A: 2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N( 1 H-pyrazol-3-yl)acetamide. The title compound (383 mg, 70%) was prepared analogously to Example 1, Step A using 1 H-pyrazol-3-amine (465 mg, 5.48 mmol) in place of 1-amino -2-methylpropane-2-ol. MS (ESI): mass calc. for C ²⁷ H ²⁶ N ⁸ O ³ S, 542.2; m/z found, 543.2 [M+H]+. 1H NMR (500 MHz, DMSO-afe) 512.36 (s, 1H), 11.36 (s, 1H), 10.81 (s, 1H), 8.65 (s, 1H), 8.14 - 8.10 (m, 2H), 7.96 (d, J = 4.1 Hz, 1H), 7.72 -7.68 (m, 1H), 7.63 -7.60 (m, 2H) , 7.30 (s, 1H), 7.13 (d, J = 4.2 Hz, 1H), 6.44 -6.41 (m, 1H), 5.41 (s, 1H), 4, 57 (s, 1H), 4.44 (s, 2H), 4.24 (s, 2H), 2.56 (d, J = 6.2 Hz, 2H), 2.23 - 2.13 (m , 2H), 2.02-1.95 (m, 1H), 1.41-1.32 (m, 2H).

[0396] Step B: 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2- yl)-N-(1H-pyrazol-3-yl)acetamide. The title compound was prepared analogously to Example 1, Step B using 2- ( 1- (( 1r,4r)-4- (cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4, 5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(1H-pyrazol-3-yl)acetamide (270 mg, 0.500 mmol) in place of 2-(1-((1r ,4phy)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl)-N-(2 -hydroxy-2-methylpropyl)acetamide and purified by basic HPLC using an Xbridge Prep OBD C ¹⁸¹ 50 mm X 30 mm, 5 pm, eluent 5% ACN/NH ⁴ OH (aq) (10 min) to give the title compound (15mg, 7%) MS (ESI): mass calcd for C ²¹ H ²² N ⁸ O, 402.5, m/z found, 403.2 [M+H]+, 1H NMR (500 MHz, DMSO -d6): 5 12.35 (s, 1H), 11.85 (s, 1H), 10.84 (s, 1H), 8.50 (s, 1H), 7.58 (d, J = 2 .3 Hz), 1H), 7.46 (d, J = 3.4 Hz, 1H), 6.72 (d, J = 3.5 Hz, 1H), 6.47 -6.39 (m, 1H), 4.64 -4.46 (m, 1H), 4.21 (s, 2H), 2.57 (d, J = 6.1 Hz, 2H), 2.45 - 2.26 (m , 2H), 2.08-1.88 (m, 5H), 1.39 (q, J = 11.7 Hz, 2H).

Reference Example 75 Synthesis and Characterization:

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-N-( 3,5-dimethylcyclohexyl)acetamide

[0397]

[0398] To a solution of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2 -yl)sodium acetate (200 mg, 0.557 mmol), 3,5-dimethylcyclohexanamine (Intermediate 4, 70.8 mg, 0.557 mmol) and DlPEA (144 mg, 1.11 mmol) in DMF (5 mL), were added PyBOP (311 mg, 0.668 mmol) and stirred at room temperature overnight. The reaction was poured into water (60ml) and extracted with CH ² Cl ² (4 X 80ml). The organic phases were combined and concentrated to dryness. The residue was purified by preparative basic HPLC using a Phenomenex Gemini 150 mm x 25 mm, 10 pm column (eluent: 40 to 70% ACN in water (0.05% NH ⁴ OH), v/v) to give the title compound (79 mg, 32% yield) as a white solid. MS (ESI): mass calc. for C ²⁶ H ³⁴ N ⁶ O, 446.28; m/z found, 447.2 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 11.84 (br s, 1H), 8.49 (s, 1H), 8.21-8.19 (m, 1H), 7.47-7, 46 (m, 1H), 6.71 (s, 1H), 4.54 -4.41 (m, 1H), 4.07 - 3.99 (m, 1H), 3.95 (s, 1H ), 3.65 - 3.40 (m, 1H), 2.60 (t, J = 5.6 Hz, 2H), 2.44 - 2.26 (m, 2H), 2.11-1, 88 (m, 5H), 1.85-1.71 (m, 2H), 1.69-1.53 (m, 2H), 1.50-1.31 (m, 3H), 1.07 - 0.95 (m, 1H), 0.87 (t, J = 6.0 Hz, 6H), 0.84 - 0.73 (m, 1H), 0.62 - 0.44 (m, 1H) .

Reference Example 76 Synthesis and Characterization:

4-(4-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl) piperidin-1-yl)benzonitrile

[0399]

[0400] Step A: 4-(4-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-2-yl)piperidin-1-yl)benzonitrile. A solution of 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1 0.70 mg, 0.16 mmol), 4-(4-formylpiperidin-1-yl)benzonitrile (69 mg, 0.32 mmol), sodium hydrosulfite (82 mg, 0.40 mmol), DMSO (1 mL) , methanol (1 mL) and water (0.5 mL) were heated in a sealed tube at 100 °C for 16 h. After cooling to room temperature, the mixture was extracted with EtOAc (3x) and CH ² Cl ² (2x). The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated to dryness to provide the title compound (90 mg, 94% yield), which was used in the next reaction without further purification. MS (ESI): mass calc. for C ³⁴ H ³³ N ⁷ O ² S, 603.24; m/z found, 604.3 [M+H]+.

[0401] Step B: 4-(4-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridine -2-yl)piperidin-1-yl)benzonitrile. A reaction mixture of 4-(4-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-aÍpyrrolo[2,3- ¿>]pyridin-2-yl)piperidin-1-yl)benzonitrile (90 mg, 0.15 mmol), 3 M NaOH aq. solution (0.12 mL, 0.36 mmol), pyrrolidine (0.050 mL, 0 0.60 mmol), MeOH (1 mL) and THF (1 mL) was stirred at room temperature for 5 h and concentrated in vacuo. The residue was purified by flash column chromatography (3-10% MeOH in CH ² Cl ² ) to give the title compound as a white solid (15 mg, 22% yield). MS (ESI): mass calc. for C ²⁸ H ²⁹ N ⁷ , 463.25; m/z found, 464.2 [M+H]+. 1H NMR (400 MHz, CDCla) = 9.18 (br s, 1H), 8.77 (s, 1H), 7.54-7.50 (m, 2H), 7.39-7.36 ( m, 1H), 6.94 -6.91 (d, J =9.1 Hz, 2H), 6.72 -6.70 (m, 1H), 4.39 (br s, 1H), 4, 09 - 3.99 (m, 2H), 3.24 - 3.09 (m, 3H), 2.76 - 2.60 (m, 2H)), 2.49 (d, J =6.1 Hz , 2H), 2.31-2.17 (m, 5H), 2.16-1.96 (m, 4H), 1.63-1.48 (m, 2H).

Reference Example 77 Synthesis and Characterization:

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzenesulfonamide

[0402]

[0403] Benzenesulfonyl chloride (69.9 mg, 0.396 mmol) was added dropwise to a solution of 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-d) hydrochloride ]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 5, 150 mg, 0.396 mmol, 91% purity), triethylamine (0.276 mL, 1.98 mmol), and CH ² Cl ² (5 mL) and stirred for 30 minutes at 10 °C. The reaction was diluted with CH ² Cl ² (10 mL), washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC (eluent: CH ² Ch: methanol, 10:1) to provide the title compound (60 mg, 33% yield) as a white solid. MS (ESI): mass calc. for C ²³ H ²⁴ N ⁶ O ² S, 448.17; m/z found, 449.1 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 11.91 (s, 1H), 8.52 (s, 1H), 8.42 (br s, 1H), 7.90-7.84 (m, 2H), 7.71-7.56 (m, 3H), 7.48 (t, J = 2.8 Hz, 1H), 6.72 (d, J = 0.8 Hz, 1H), 4, 66 -4.52 (m, 1H), 4.36 (s, 2H), 2.60 (d, J = 5.6 Hz, 2H), 2.42 - 2.24 (m, 2H), 2 .11-1.88 (m, 5H), 1.48-1.30 (m, 2H).

Reference Example 78 Synthesis and Characterization:

N- (( 1S ,4R)-Bicyclo[2,2,1]heptan-2-yl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo [4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide

[0404]

[0405] To a solution of 2-(1 -((ir,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- Sodium 2-yl)acetate (intermediate 4, 100 mg, 0.278 mmol) and (1S,4R)-bicyclo[2,2,1]heptan-2-amine (82.2 mg, 0.557 mmol) in d Mf ( 0.8 mL) PyBOP (217 mg, 0.417 mmol) and DIPEA (0.192 mL, 1.11 mmol) were added and stirred at room temperature for 42 h. The reaction was concentrated to dryness and the residue was purified by flash column chromatography (12 g silica gel column, 50-100% EtOAc in heptanes then 10% MeOH in DCM) and reverse phase acidic HPLC using a 100 x 30 mm Varian Pursuit XRs5 Diphenyl column (eluent: 10-90% CH ³ CN in H ² O, 0.1% TFA) to provide the TFA salt. This material was dissolved in 10% MeOH/CH ² Cl ² and passed through a 500 mg SILICYCLE SPE-R66030B-03P carbonate column (solid phase extraction cartridge with SiliaBond acid scavenger) to remove TFA. and eluted with 10% MeOH in CH ² Cl ² to give the title compound (61 mg, 51% yield) as a white solid. MS (ESI): mass calc. for C ²⁵ H ³⁰ N ⁶ O, 430.25; m/z found, 431.3 [M+H]+. 1H NMR (400 MHz, CDCla) = 11.90 (br s, 1H), 8.81 (s, 1H), 7.61 (br s, 1H), 7.52 (br s, 1H), 6 .76 (d, J = 3.0 Hz), 1H), 4.74 (br s, 1H), 4.18 - 3.99 (m, 2H), 2.71 - 2.48 (m, 1H ), 2.46 - 2.35 (m, 3H), 2.31 -1.95 (m, 9H), 1.58-1.22 (m, 7H), 1.18-1.05 (m , 1H), 0.75 (td, J =3.6, 13.0 Hz, 1H).

Reference Example 79 Synthesis and Characterization:

2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(4-( difluoromethoxy)benzyl)acetamide

[0406]

[0407] Step A: 2-(1 -((7r,4rM-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)-N-(4-(difluoromethoxy)benzyl)acetamide The title compound (90 mg, 71%) was prepared using conditions analogous to those described in Example 48, Step A, using Intermediate 3 ( 100 mg, 0.200 mmol) and W-(4-(difluoromethoxy)benzyl amine (312 mg, 1.80 mmol) in place of phenylmethanamine. MS (ESI): mass calculated for C ³² H ³⁰ F ² N ⁶ O ⁴ S , 632.2, m/z found, 633.2 [M+H]+.

[0408] Step B: 2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)- W-f4-(difluoromethoxy)benzyl)acetamide The title compound (53 mg, 75%) was prepared using analogous conditions to those described in Example 48, Step B using 2-(1-((1R,4R)-4 -(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(4-(difluoromethoxy)benzyl) acetamide (90 mg, 0.14 mmol) in place of N-benzyl-2-(1-((7R,4Rj-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4, 5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide Purification was performed by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 10 -90% CH ³ CN in H ² O, 0.1% TFA) MS (ESI): mass calcd for C ²⁶ H ²⁶ F ² N ⁶ O ² , 492.21, m/z found, 493.2 [M+H]+ 1H NMR (400 MHz, CD ³ OD) 5 = 8.53 (s, 1H), 7.47 (d, J =3.5 Hz, 1H), 7.36 (d, J =8.5 Hz , 2H), 7.10 (d, J =8.6 Hz, 2H), 6.82 (d, J =3.6 Hz, 1H), 6.79 (s, 1H), 4.44 (b r s, 1H), 4.39 (s, 2H), 4.12 (s, 2H), 2.62 - 2.48 (m, 2H), 2.50 (d, J =6.1 Hz, 2H ), 2.09-1.97 (m, 5H), 1.44-1.28 (m, 2H).

Reference Example 80 Synthesis and Characterization:

1-((7r,4r1-4-(cyanomethyl)cyclohexyl)-W-('(3-hydroxyoxetan-3-yl)methyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridine-2-carboxamide

[0409]

[0410] The title compound (37 mg, 45% yield) was prepared using Intermediate ⁶ and conditions analogous to those described in Example 50, step A, and using 3-(aminomethyl)oxetan-3-ol instead. of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²¹ H ²⁴ N ⁶ O ³ , 408.19; m/z found, 409.2 [M+H]+. 1H NMR (400 MHz, CDCta): 10.40 (s, 1H), 8.67 (s, 1H), 8.17 (s, 1H), 7.36 (d, J= 3.5 Hz, 1H), 6.72 (d, J = 3.5 Hz, 1H), 6.03 - 5.53 (m, 1H), 5.33 - 5.06 (m, 1H), 4.62 (d , J= 6.9 Hz, 2H), 4.55 -4.38 (m, 2H), 3.86 (d, J = 6.0 Hz, 2H), 2.66 - 2.42 (m, 2H), 2.35 (d, J = ^{6, 6} Hz, 2H), 2.05-1.95 (m, 5H), 1.51-1.32 (m, 2H).

Reference Example 81 Synthesis and Characterization:

2-(( 1r,4r)-4- ( 2- ( 3-Methyl- 1 H-pyrazol-5-yl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin-1 ( ⁶ H)-yl)cyclohexyl)acetonitrile

[0411]

[0412] Step A: 2-((1r,4r)-4-(2-(3-Methyl-1H-pyrazol-5-yl)-6-(phenylsulfonyl)imidazo[4,5-a(|pyrrolo [2,3-b]pyridin-1( 6H)- yl)cyclohexyl)acetonitrile To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1- (phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (intermediate 1214 mg, 0.487 mmol) and 3-methyl-1 H-pyrazol-5-carbaldehyde (120 mg , 1.09 mmol) as solids DMSO (2.2 mL), MeOH (2.2 mL) and distilled water (1.1 mL) were added resulting in a yellow mixture Sodium hydrosulfite (298 mg) was added , 1.71 mmol) as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100 °C and heated for 3 h. The vial was cooled to room temperature and added to vigorously stirred water ( 75 mL), resulting in an emulsion-like mixture. The mixture was filtered through a microporosity fritted funnel to trap any solids. The filter cake was rinsed with water and air dried for overnight and then further dried under high vacuum for ¹ h to provide the title compound (238 mg, 97% yield), which was used in the next reaction without further purification. MS (ESI): mass calc. for C ²⁶ H ²⁵ N ⁷ O ² S, 499.18; m/z found, 500.2 [M+H]+. 1H NMR (500 MHz, chloroform-d) 8.94 (s, 1H), 8.28-8.18 (m, 2H), 7.84 (d, J = 4.0 Hz, 1H), 7 .60 - 7.52 (m, 1H), 7.52 - 7.42 (m, 2H), 6.90 (d, J = 4.1 Hz, 1H), 6.73 (s, 1H), 5.66 (s, 1H), 2.50-2.33 (m, 7H), 2.05 (sd, J = 29.0, 12.9 Hz, 5H), 1.57-1.39 ( m, 2H).

[0413] Step B: 2-((1r,4r)-4-(2-(3-Methyl-1H-pyrazol-5-yl)imidazo[4,5-a]pyrrolo[2,3-b] pyridin-1( ^6H )-yl)cyclohexyl)acetonitrile. The title compound was prepared using analogous conditions to those described in Example 1, Step B using 2- (( 1r,4r) -4-(2-(3-Methyl-1H-pyrazol-5-yl)-6 -(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1 ( ⁶ H)-yl)cyclohexyl)acetonitrile (235 mg, 0.47 mmol) in place of 2-(1- ((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-blpyridin-2-yl)-W-(2 -hydroxy-2-methylpropyl)acetamide and the residue was purified by flash column chromatography (2 ⁿ 0-8% NH3-MeOH/EA, 10 CV) to give the title compound (143 mg, 81%). MS (ESI): mass calc. for C ²⁰ H ²¹ N ⁷ , 359.19; m/z found, 360.2 [M+H]+. 1H NMR (500 MHz, DMSO-ds): 513.03 (s, 1H), 11.91 (s, 1H), 8.60 (s, 1H), 7.50 (t, J = 3.0 Hz , 1H), 6.82 -6.72 (m, 1H), 6.64 (s, 1H), 5.90 - 5.57 (m, 1H), 2.60 (d, J = 6.0 Hz, 2H), 2.56-2.41 (m, 2H), 2.34 (s, 3H), 2.13-1.98 (m, 3H), 1.98-1.87 (m, 2H), 1.42-1.26 (m, 2H).

Reference Example 82 Synthesis and Characterization:

4-cyano- n-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin-2- yl)methyl)benzamide

[0414]

[0415] HATU (155 mg, 0.409 mmol) was added to a solution of 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-a]pyrrolo[2,3- b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (Intermediate 5, 150 mg, 0.409 mmol, 94% purity), 4-cyanobenzoic acid (60.2 mg, 0.409 mmol), DIEA (0.356 mL, 2, 04 mmol) and CH ² Cl ² (5 mL) and stirred for 1 hour at 10 °C. The reaction was diluted with CH ² Cl ² (10 mL), washed with water (10 mL) and concentrated to dryness. The residue was purified by preparative HPLC using a Phenomenex Gemini 150 mm x 25 mm, 10 gm column (eluent: 30% to 60% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (130 mg, 71% yield) as a white solid. MS (ESI): mass calc. for C ²⁵ H ²³ N ⁷ O, 437.20; m/z found, 438.2 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 11.89 (s, 1H), 9.47 (t, J = 5.2 Hz, 1H), 8.55 (s, 1H), 8.07 ( d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.47 (t, J= 2.8 Hz, 1H), 6.72 (s, 1H), 4.93 (d, J= 5.6 Hz, 2H), 4.69 -4.56 (m, 1H), 2.57 (d, J= 6.0 Hz, 2H), 2, 43-2.28 (m, 2H), 2.06-1.84 (m, 5H), 1.43-1.27 (m, 2H).

Reference Example 83 Synthesis and Characterization:

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-W-( tetrahydro-2H-thiopyran-4-yl)acetamide

[0416]

[0417] Step A: 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)-N-(tetrahydro-2H-thiopyran-4-yl)acetamide The title compound was prepared using analogous conditions to those described in Example 48, step A using tetrahydro-2H-thiopyran-4 -amine in place of phenylmethanamine to provide the title compound (85 mg, 75% yield). MS (ESI): mass calc. for C ²⁹ H ³² N ⁶ O ³ S ² , 576.20; m/z found, 577.2 [M+H]+.

[0418] Step B: 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin-2 -yl)-W-(tetrahydro-2H-thiopyran-4-yl)acetamide The title compound (30 mg, 47% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2- (1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(tetrahydro-2H-thiopyran-4-yl)acetamide (85 mg, 0.15 mmol) in place of 2- ( 1- (( 1r,4r)-4- (cyanomethyl)cyclohexyl)-6-( phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide Purification was performed by chromatography on flash column (12 g silica gel column, 2-10% MeOH in DCM) and then reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 5-95% CH ³ CN in water, with 0.1% TFA) Fractions were concentrated and dissolved in 10% MeOH in DCM, passed through a column SILICYCLE SPE-R66030B-03P carbonate 500 mg na to remove TFA and eluted with 10% MeOH in DCM. MS (ESI): mass calc. for C ²³ H ²⁸ N ⁶ OS, 436.20; m/z found, 437.3 [M+H]+. 1H NMR (400 MHz, CDCh) 5 = 11.35 (br s, 1H), 8.79 (s, 1H), 7.69 (br s, 1H), 7.50 (t, J = 2.8 Hz, 1H), 6.79 - 6.73 (m, 1H), 4.69 (br s, 1H), 4.03 (s, 2H), 3.89 - 3.75 (m, 1H), 2.76-2.53 (m, 5H), 2.43 (d, J =6.6 Hz, 2H), 2.27-1.98 (m, 7H), 1.90 (br s, 1H ), 1.65-1.44 (m, 4H).

Reference Example 84 Synthesis and Characterization:

1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-W-('1-methylpiperidin-4-yl)-1,6-d¡h¡d¡d¡m¡dazo[4,5-a( ]p¡rrolo[2,3-b]p¡r¡d¡na-2-carboxam¡da

[0419]

[0420] The title compound (20 mg, 21% yield) was prepared using Intermediate 6 and analogous conditions to those described in Example 50, step A using 1-methylpiperidine-4-amine in place of 3-phenylpyrroline- 3-ol. MS (ESI): mass calc. for C ²³ H ²⁹ N ⁷ O, 419.24; m/z found, 420.3 [M+H]+. 1H NMR (500 MHz, CD ³ OD): 58.66 (s, 1H), 7.53 (d, J = 3.5 Hz, 1H), 6.89 (d, J = 3.5 Hz, 1H ), 5.54-5.44 (m, 1H), 4.05 - 3.83 (m, 1H), 2.93 (d, J = 11.8 Hz, 2H), 2.71 - 2, 50 (m, 4H), 2.37 - 2.19 (m, 5H), 2.18-1.99 (m, 7H), 1.82-1.69 (m, 2H), 1.57- 1.39 (m, 2H).

Example 85 Synthesis and characterization:

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl)-N- ((1-hydroxycyclopropyl)methyl)acetamide

[0421]

[0422] A solution of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2 -yl)acetate (intermediate 4, 300 mg, 0.835 mmol), 1-(aminomethyl)cyclopropanol (72.7 mg, 0.835 mmol), DIPEA (216 mg, 1.67 mmol) and DMF (5 mL) was stirred at 0 °C for 1 h. PyBrOP (467 mg, 1.00 mmol) was then added and stirred at room temperature overnight. The mixture was quenched with 10 mL of water and purified by preparative basic HPLC using a Kromasil column 150 mm x 25 mm, 10 pm (eluent: water (0.05% v/v ammonium hydroxide)-5% to 35% ACN, v/v) to give the title compound (84 mg, 25% yield) as a white solid MS (ESI): mass calcd for C ²² H ²⁶ N ⁶ O ² , 406.21, m/z found, 407.2 [M+H]+ 1H NMR ( 400 MHz, DMSO-afe): 5 11.53 (br s, 1H), 8.50 (s, 1H), 8.03 - 7.93 (m, 1H), 7.44 - 7.40 (m , 1H), 6.74 -6.71 (m, 1H), 5.04 (s, 1H), 4.58 -4.49 (m, 1H), 4.02 (s, 2H), 3, 29 (d, J= 6.0Hz, 2H), 2.55 (d, J= 6.0Hz, 2 H), 2.45 - 2.31 (m, 2H), 2.10-1.97 (m, 5H), 1.50-1.37 (m, 2H), 0.62 - 0.55 ( m, 2H), 0.55-0.48 (m, 2H).

Reference Example 86 Synthesis and Characterization:

N- (( 1- (( 1r,4r)-4- ( C'¡anomethyl)cyclohexyl)-1 ,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) methyl)acetimidamide

[0423]

[0424] Step A: n- (( 1 -((1r,4r)-4-(C¡anomet¡l)c¡clohex¡l)-6-(phenylsulfon¡l)-1,6-d ¡h¡dro¡midazo[4,5-d]pyrrolo[2,3-b]p¡r¡d¡n-2-yl)methyl)acetimidamide. A solution of 2-((1r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile (intermediate 8, 52 mg, 0.11 mmol), acetimidamide hydrochloride (21 mg, 0.22 mmol) and K ² CO ³ (49 mg, 0.36 mmol) in DMF ( ^1.4 mL ) was stirred at room temperature for 15 H. The reaction was filtered to remove the solid and the filtrate was concentrated to dryness. The residue was partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to provide the title compound (47 mg, 86% yield) as a white solid. MS (ESI): mass calc. for C ²⁵ H ²⁷ N ⁷ O ² S, 489.19; m/z found, 490.2 [M+H]+. MS (ESI): mass calc. for C ²⁵ H ²⁷ N ⁷ O ² S, 489.6; m/z found, 490.2 [M+H]+. 1H NMR (400 MHz, CDCh) 5 = 8.82 (s, 1H), 8.23 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 4.0 Hz, 1H) , 7.60 -7.53 (m, 1H), 7.52 - 7.44 (m, 2H), 6.84 (d, J =4.0 Hz, 1H), 4.56 -4.52 (m, 3H), 2.41 (d, J =6.57 Hz, 2H), 2.39 - 2.25 (m, 2H), 2.20 - 2.09 (m, 2H), 2, 05-1.90 (m, 6H), 1.56-1.41 (m, 2H).

[0425] Step B: N- (( 1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin- 2-yl)methyl)acetimidamide A solution of N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a( |pyrrolo[2,3-b/pyridin-2-yl)methyl)acetimidamide (45 mg, 0.092 mmol) in THF (1 mL) and MeOH (1 mL) was treated with aq. 3N NaOH (0.15 mL). , 0.45 mmol) at room temperature for 18 h and concentrated.The residue was purified by reverse phase HPLC (10-90% CH ³ CN in H ² O, 0.1% TFA).Fractions were concentrated and the residue was partitioned between NaHCO3 (aq) and n-BuOH (x 3).The organic layer was dried (Na2SO4), filtered and concentrated to a white solid.This solid was washed with CH ² Cl ² and dried to give the title compound (31 mg, 97% yield) MS (ESI): mass calcd for C ¹⁹ H ²³ N ⁷ , 349.20, m/z found, 350.3 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 5 = 8.54 (s, 1H), 7.49 (d, J =3.5 Hz, 1H), 6.85 (d, J =3.5 Hz, 1H), 4.69 (s, 2H), 4.51 (br s, 1H), 2.55 (d, J =6.1 Hz, 4H), 2.19 - 2.02 (m, 8H), 1.56-1 .42 (m, 2H).

Reference Example 87 Synthesis and Characterization:

2-(( 1r,4r)-4-(2-(2-(4-Benzylpiperidin-1 -yl)-2-oxoethyl)imidazo[4,5-a(|pyrrolo[2,3-bjpyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile and its trifluoroacetic acid salt

[0426]

[0427] Step A: 2-((1r,4r)-4-(2-(2-(4-Benzylpiperidin-1 -yl)-2-oxoethyl)-6-(phenylsulfonyl)imidazo[4,5-a ^pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile The title compound was prepared using analogous conditions to those described in Example 48, step A using 4-benzylpiperidine in place of phenylmethanamine to give the title compound (38 mg, 63% yield). MS (ESI): mass calc. for C ³⁶ H ³⁸ N ⁶ O ³ S, 634.27; m/z found, 635.2 [M+H]+.

Step B: 2-(( 1r,4r)-4-(2-(2-(4-Benzylpiperidin-1 -yl)-2-oxoethyl)imidazo[4,5-a(|pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile as its trifluoroacetic acid salt The free base compound was prepared using analogous conditions as described in Example 48, step B using 2-((1r,4r)- 4-(2-(2-(4-benzylpiperidin-1-yl)-2-oxoethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H) -yl)cyclohexyl)acetonitrile instead of N-benzyl-2- ( 1- (( 1r,4r)-4- ( c'ianomethyl)cyclohexyl)-6- (phenylsulfonyl)-1,6-dihydroimidazo[4,5 -d]pyrrolo[2,3-b]pyridin-2-yl)acetamide Purification by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 10 - 90% CH ³ CN in H ² 0, 0.1% TFA) provided the title compound (11 mg, 38% yield) as its trifluoroacetic acid salt MS (ESI): mass calcd for C ³⁰ H ³⁴ N ⁶ O, 494.28, m/ z found, 495.3 [M+H]+.1H NMR (400 MHz, CD ³ OD) 5 = 8.81 (br s, 1H), 7.74 (d, J =3.5 Hz, 1H) , 7.30 - 7.21 (m, 2H), 7.20 - 7.14 (m, 3H), 7.08 (d, J =3.0 Hz, 1H), 4.56 (br s, 1H), 4.53 -4.42 ( m, 1H), 4.10 (br d, J =12.6 Hz, 1H), 3.28 - 3.16 (m, 1H), 2.77 - 2.66 (m, 1H), 2, 64 - 2.48 (m, 6H), 2.22 - 2.08 (m, 6H), 1.95-1.68 (m, 4H), 1.59 1.44 (m, 2H), 1 .37-1.11 (m, 2H).

Reference Example 88 Synthesis and Characterization:

2-((1r,4r)-4-(2-(4-Hydroxy-4-(pyridin-2-yl)piperidine-1-carbonyl)imidazo[4,5-a]pyrrolo[2,3-b] pyridin-1 ( 6H)- yl)cyclohexyl)acetonitrile

[0428]

[0429] The title compound (11 mg, 11% yield) was prepared using Intermediate 6 and conditions analogous to those described in Example 50, step A using 4-(pyridin-2-yl)piperidin-4-ol instead of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²⁷ H ²⁹ N ⁷ O ² , 483.24; m/z found, 484.3 [M+H]+. 1H NMR (500 MHz, CD ³ OD): 58.65 (s, 1H), 8.55 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 4.6 Hz, 0 .5H), 8.12 (d, J = 7.7 Hz, 0.5H), 7.86 (t, J = 7.7 Hz, 1H), 7.76 (d, J = 7.9 Hz , 1H), 7.55 (d, J = 3.5 Hz, 1H), 7.44 (dd, J = 7.8, 4.8 Hz, 0.5H), 7.37 - 7.24 ( m, 1H), 6.89 (d, J = 3.5 Hz, 1H), 5.76 (s, 0.5H), 3.84 - 3.72 (m, 2H), 3.57 - 3 .44 (m, 1H), 2.68 (s, 1H), 2.61 - 2.32 (m, 6H), 2.27 - 2.14 (m, 4H), 2.12-1.99 (m, 1H), 1.96-1.84 (m, 1H), 1.76-1.66 (m, 1H), 1.64-1.50 (m, 2H).

Reference Example 89 Synthesis and Characterization:

2-((ir,4r)-4-(2-(2-(Methylamino)pyrimidin-4-yl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile

[0430]

[0431] Step A: 2-(( 7r,4r)-4-(2-(2-(Methylthio)pyrimidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)cyclohexyl)acetonitrile. A solution of 2-((7r,4r,)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile ( Intermediate 1.400 mg, 1.00 mmol), 2-(methylthio)pyrimidine-4-carbaldehyde (463 mg, 3.00 mmol), sodium dithionite (523 mg, 3.00 mmol), DMSO (2.5 mL) and water (0.15ml). heated at 100 °C for 3 hours. Water (20ml) was added which caused a precipitate to form and filtered to collect the precipitate. The precipitate was recrystallized from 10% acetone/CH ² Cl ² to give a crude product (200 mg). This material was dissolved in MeOH/THF/NaOH (1M) (3ml/3ml/3ml) and heated at 80°C for 1h. The reaction was concentrated to dryness and partitioned between CH ² Cl and H ² O (10 mL/10 mL). The organic layer was concentrated to dryness and purified by flash column chromatography (10% MeOH in CH ² Ch) to give the title compound (100 mg). MS (ESI): mass calc. for C ²¹ H ²¹ N ⁷ S, 403.16; m/z found, 404.2 [M+H]+.

[0432] Step B: 2-(( ír,4r)-4-(2-(2-(Methylamino)pyrmidin-4-yl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin -1(6H)-yl)cyclohexyl)acetonitrile A solution of 2-((7r,4r)-4-(2-(2-(methylthio)pyrimidin-4-yl)imidazo[4,5-¿]pyrrolo [2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (100 mg, 0.248 mmol) and 3-chlorobenzoperoxoic acid (128 mg, 0.743 mmol) in THF (10 mL) was stirred for 3 h. Methylamine (2M in MeOH, 2 mL) was then added and heated to 100 C for 1 h The reaction was concentrated to dryness and partitioned between CH ² Cl/water (5 mL/5 mL), the Organic phase was collected and concentrated to dryness The residue was purified by flash column chromatography to give the title compound (9 mg, 9% yield) MS (ESI): mass calcd for C ²¹ H ²² N ⁸ , 386.20, m/z found, 387.1 [M+H]+ 1H NMR (500 MHz, CDCL): 59.86 (s, 1h), 8.82 (s, 1H), 8, 41 (d, J = 5.1 Hz, 1H), 7.51 - 7.27 (m, 2H), 6.81 -6.63 (m, 1H), 6.07 - 5.48 (br, 1H), 5.23 (s 1H), 3.03 (d, J = 5.0 Hz, 3H), 2, 71 - 2.50 (m, 2H), 2.37 (d, J = 6.3 Hz, 2H), 2.18 - 2.01 (m, 5H), 1.48-1.31 (m, 2H).

Reference Example 90 Synthesis and Characterization:

2-(( 7r,4r^-4-(2-(2-Oxo-2-(piperidin-1 -yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile

[0433]

[0434] Step A: 2-((7r,4r)-4-(2-(2-Oxo-2-(piperidin-1 -yl)ethyl)-6-(phenylsulfonyl)imidazo[4,5-d] pyrrolo[2,3-blpyridin-1(6H)-yl)cyclohexyl)acetonitrile as its trifluoroacetate salt. A solution of 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)ethyl acetate (intermediate 3, 124 mg, 0.250 mmol), piperidine (1.0 mL, 10 mmol), and NH ⁴ NO ³ (20 mg, 0.25 mmol) under Ar was microwaved to 50 °C for 5 h and 70 °C for 5 h. After concentration, the residue was purified by RF-HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 10 - 100% CH ³ CN in H ² O, 0.1% TFA) to give the compound of the title (90.0 mg, 56%) as a clear oil. MS (ESI): mass calc. for C ²⁹ H ³² N ⁶ O ³ S, 544.23; m/z found, 545.3 [M+H]+.

[0435] Step B: 2-((1r,4r)-4-(2-(2-Oxo-2-(piperidin-l-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3- b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile as its trifluoroacetate salt. A solution of 2-((1r,4r)-4-(2-(2-oxo-2-(piperidin-1-yl)ethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile as its trifluoroacetate salt (90 mg, 0.14 mmol) in THF (1 mL) and MeOH (1 mL) was treated with 3N NaOH (0 0.14 mL, 0.41 mmol) overnight at room temperature. A few drops of TFA were added and the solvents removed in vacuo to provide a clear oil. This residue was purified by RF-HPLC using a 100 x 30 mm Varian Pursuit XRs5 Diphenyl column (eluent: 10-90% CH ³ CN in H ² O, 0.1% TFA) to provide the title compound as a TFA salt, which was partitioned between CH ² Cl ² and saturated aqueous NaHCO ³ solution. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound (19 mg, 47%) as an off-white solid. MS (ESI): mass calc. for C ²³ H ²⁸ N ⁶ O, 404.23; m/z found, 405.3 [M+H]+. 1H NMR (400 MHz, CDCh) 5 = 11.67 (br s, 1H), 8.78 (s, 1H), 7.46 (br s, 1H), 6.73 (d, J = 2.5 Hz, 1H), 4.82 -4.72 (m, 1H), 4.22 -4.16 (m, 1H), 3.75 - 3.67 (m, 2H), 3.60 - 3, 50 (m, 2H), 2.64 - 2.46 (m, 2H), 2.40 (d, J =6.6 Hz, 2H), 2.33 (br s, 1H), 2.16 ( d, J =14.7 Hz, 2H), 2.10-1.98 (m, 3H), 1.63-1.55 (m, 2H), 1.55-1.37 (m, 6H) .

Reference Example 91 Synthesis and Characterization:

2-((1r,4r)-4-(2-(4'-(Methylsulfonyl)-[1,1'-biphenyl]-4-yl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0436]

[0437] Step A: 2-((1r,4r)-4-(2-(4'-(Methylsulfonyl)-[1,1'-biphenyl]-4-yl)-6-(phenylsulfonyl)imidazo[4 ,5-a]pyrrolo[2,3-b]pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. To a solution of 2-((1r,4r)-4-((5-nitro-l-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 120 mg, 0.273 mmol) in ^{dM sO} (2.32 mL) and MeOH (0.465 mL) in a microwave vial was added 4'-(methylsulfonyl)[1,1'-biphenyl]-4-carbaldehyde (101 mg, 0.388 mmol), followed by sodium hydrosulfite (140 mg, 0.683 mmol). The vial was stoppered and heated at 100 °C over the weekend. After cooling to room temperature, the reaction was diluted with water (5 mL) and stirred for 5 minutes. The tan precipitate that formed was collected by filtration, washed with water (50 ml) and allowed to dry completely. The precipitate was dissolved in EtOAc, transferred to a round bottom flask, and then concentrated to dryness to provide the title compound as a tan solid, which was used without further purification. MS (ESI): mass calc. for C ³⁵ H ³¹ N ⁵ O ⁴ S ² , 649.18; m/z found, 650.3 [M+H]+.

[0438] Step B: 2-(( 7r,4rJ-4-(2-(4'-(Meth¡lsulfonyl)-[1,1'-biphenyl]-4-yl)imidazo[4,5-d| pyrrolo[2,3-b]pyridin-1( 6H)-yl )cyclohexyl)acetonitrile The title compound (80 mg, 58% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2-((1r,4r)-4-(2-(4'-(Met¡lsulfon¡l)-[1,1'-b¡fen¡l]-4-¡l)-6-(fen¡ lsulfon¡l)¡m¡dazo[4,5-d|p¡rrolo[2,3-b]p¡r¡d¡n-1(6H)-¡l)c¡clohex¡l)aceton¡tr ¡lo (177 mg, 0.272 mmol) instead of 2- ( 1- (( 1r,4r)-4- (cyanomethyl)c¡clohex¡l)-6-(phenylsulfon¡l)- 1,6-d¡h¡dro¡m¡dazo[4,5-d]p¡rrolo[2,3-b]p¡r¡d¡n-2-¡l)-W-('2- hydroxy¡-2-methylpropyl)acetamide The crude material was purified on a 12 gram silica gel column using 0 to 10% MeOH in DCM to provide the title compound MS (ESI): mass calc. for C ²⁹ H ²⁷ N ⁵ O ² S, 509.19, m/z found, 510.1 [M+H]+ 1H NMR (400 MHz, DMSO-d6): 12.01 (s, 1H) , 8.67 (s, 1H), 8.13 - 8.03 (m, 4H), 8.00 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 7.9 Hz, 2H), 7.59 - 7.49 (m, 1H ), 6.81 (d, J = 3.3 Hz, 1H), 4.57 -4.35 (m, 1H), 3.30 (s, 3H), 2.55 (d, J = 6, 2 Hz, 2H), 2.49-2.38 (m, 2H), 2.11-1.90 (m, 5H), 1.37-1.19 (m, 2H).

Reference Example 92 Synthesis and Characterization:

2-((1r,4r)-4-(2-(4-benzo¡lfen¡l)¡m¡dazo[4,5-d]p¡rrolo[2,3-b]p¡r¡d¡ n-1 ^HHOcyclohexyOacetonitrile

[0439]

[0440] Step A: 2-((1r,4r)-4-(2-(4-Benzo¡lfen¡l)-6-(fen¡lsulfon¡l)¡m¡dazo[4,5-d] p¡rrolo[2,3-b]p¡r¡d¡n-1 ( 6H)- iOcyclohexyOacetonitrile.To a solution of 2-((1r,4r)-4-((5-nitro-1 -(phenylsulfonyl )-1H-pyrrolo[2,3-b]pyridin-4-iOamino^iclohexyOacetonitrile (intermediate 1, 121 mg, 0.275 mmol) in ^{dM sO} (2.34 mL) and MeOH (0.468 mL) in a vial Microwave 4-benzoylbenzaldehyde (63.6 mg, 0.303 mmol) was added, followed by sodium hydrosulfite (141 mg, 0.688 mmol).The vial was stoppered and heated at 100°C over the weekend.After cooling At room temperature, the reaction was diluted with water (5ml) and stirred for 5 minutes.The tan precipitate that formed was collected by filtration, washed with water (50ml) and allowed to dry completely.The solid was collected in round bottom by dissolving in EtOAc.The organic phase was then concentrated to dryness to provide the title compound as a tan solid, which was used without further purification.MS (ESI): mass calc. for C ³⁵ H ²⁹ N ⁵ O ³ S, 599.20; m/z found, 600.3 [M+H]+.

[0441] Step B: 2-(( 1r,4r)-4-(2-(4-benzo¡lfen¡l)¡m¡dazo[4,5-d]p¡rrolo[2,3-b] p¡r¡d¡n-1(6H)-¡lo)c¡clohex¡l)aceton¡tr¡lo. The title compound (56 mg, 45% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2-((1r,4r)-4-(2-(4-Benzo¡lfen¡ l)-6-(fen¡lsulfon¡l)¡m¡midazo[4,5-d]pyrro[2,3-¿>]p¡r¡d¡n-1(6H)-iOcyclohexyOacetonitrile (165 mg, 0.275 mmol) instead of 2-(1-((1r,4r)-4-(cyanomethyl)c¡clohex¡l)-6-(phenylsulfon¡l)-1,6- dihydroimidazo^^-adpyrrolo^^-blpyridin^-iO-N-^-hydroxy^-methylpropyOacetamide.The crude material was purified on a 4 gram silica gel column using 0-100% EtOAc in heptane.Then, the resulting material was triturated with acetonitrile to provide the title compound MS (ESI): mass calcd for C ²⁹ H ²⁵ N ⁵ O, 459.21, m/z found, 460.2 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 12.03 (s, 1H), 8.68 (s, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.91 ( d, J = 8.1 Hz, 2H), 7.84 (d, J = 7.5 Hz, 2H), 7.76 - 7.71 (m, 1H), 7.67 - 7.59 (m , 2H), 7.58 - 7.52 (m, 1H), 6.84 -6.79 (m, 1H), 4.52 -4.37 (m, 1H), 2.59 - 2.51 (m, 4H), 2 0.05-1.94 (m, 5H), 1.39-1.20 (m, 2H).

Example 93 Synthesis and characterization:

2-((1r,4r)-4-(2-(2-(4-(2-Hydrox¡propan-2-¡l)p¡per¡d¡n-1-¡l)-2- oxoet¡l)¡m¡dazo[4,5-d|p¡rrolo[2,3-b]p¡r¡d¡n-1(6H)-yl)cyclohexyl)acetonitrile

[0442]

[0443] To a solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-c/]pyrrolo[2,3-b]pyridine -2-yl)acetate (Intermediate 4.65 mg, 0.181 mmol) and 2-(piperidin-4-yl)propan-2-ol (65.0 mg, 0.362 mmol) in DMF (2 mL) were added to PyBOP ( 152 mg, 0.292 mmol) and DIPEA (0.10 mL, 0.58 mmol) and stirred at room temperature for 64 h. The reaction was concentrated to dryness and the residue was purified by reverse phase acidic HPLC to provide impure product. This material was partitioned between CH ² Cl ² and saturated NaHCO3, collecting the organic layer. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to dryness. This material was purified by flash column chromatography using 5-10% MeOH in DCM as eluant to provide the title compound (9 mg, 11% yield) as a foam. MS (ESI): mass calc. for C ²⁶ H ³⁴ N ⁶ O ² , 462.27; m/z found, 463.4 [M+H]+. 1H NMR (400 MHz, CDCla) = 10.72 (br s, 1H), 8.75 (s, 1H), 7.42 (t, J =2.8 Hz, 1H), 6.75-6 .70 (m, 1H), 4.76 -4.64 (m, 2H), 4.44 (d, J =12.6 Hz, 1H), 4.23 -4.13 (m, 2H), 3.04 (sd, J =2.5, 13.1 Hz, 1H), 2.61 - 2.46 (m, 3H), 2.42 (d, J =6.6 Hz, 2H), 2 .25-1.95 (m, 4H), 1.94-1.67 (m, 4H), 1.66-1.43 (m, 2H), 1.27-1.09 (m, 2H) , 1.14 (d, J =3.5Hz, 6H).

Reference Example 94 Synthesis and Characterization:

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 2-cyclopropylacetamide

[0444]

[0445] HATU (155 mg, 0.409 mmol) was added to a solution of 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-a]pyrrolo[2,3- b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 5, 150 mg, 0.409 mmol, 94% purity), cyclopropylacetic acid (40.9 mg, 0.409 mmol), DIEA (0.356 mL, 2.04 mmol ) and CH ² Cl ² (5 mL) and stirred for 1 hour at 10 °C. The reaction was diluted with CH ² Cl ² (10 mL), washed with water (10 mL) and concentrated to dryness. The residue was purified by preparative HPLC using a 150 mm x 25 mm Gemini column, 5 pm (eluent: 20% to 50% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ). to provide the title compound (45 mg, 28% yield) as a white solid. MS (ESI): mass calc. for C ²² H ²⁶ N ⁶ O, 390.22; m/z found, 391.2 [M+H]+. 1H NMR (400 mHz, DMSO-afe): 11.89 (s, 1H), 8.55 (s, 1H), 8.46 (t, J = 5.6 Hz, 1H), 7.48 (t, J = 2.4 Hz, 1H), 6.72 (s, 1H), 4.69 (d, J = 5.6 Hz, 2H), 4.62 -4.49 (m, 1H) , 2.59 (d, J = 6.0 Hz, 2H), 2.41 - 2.28 (m, 2H), 2.06 (d, J = 6.8 Hz, 2H), 2.04- 1.87 (m, 5H), 1.45-1.30 (m, 2H), 1.05 - 0.94 (m, 1H), 0.46 - 0.40 (m, 2H), 0, 16 - 0.09 (m2, 2H).

Reference Example 95 Synthesis and Characterization:

(£Z)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2- yl)methyl)-2-cyclohexyl-N'-hydroxyacetimidamide

[0446]

[0447] Step A: (£Z)-2-cyclohexylacetaldehyde oxime. A solution of 2-cyclohexylacetaldehyde (1.0 g, 7.9 mmol), hydroxylamine hydrochloride (0.551 g, 7.92 mmol), sodium acetate (1.30 g, 15.8 mmol), and ethanol (20 mL ) was stirred at room temperature for 18 hours. The reaction was concentrated to dryness and treated with water (50ml) and extracted with ethyl acetate (100ml X 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to provide the title compound (1.30 g, 116% yield), which was used in the next step without purification. 1H R ^m N (400 MHz, CDCh) 53.63 (qd, J = 7.2, 9.2 Hz, 1H), 3.49 (qd, J = 7.29.2 Hz, 1H), 2.15 - 2.04 (m, 1H), 1.76-1.62 (m, 4H), 1.50 (s, 1H), 1.20 (t, J = 7.2 Hz, 4H), 1.10 - 0.80 (m, 2H).

[0448] Step B: (£Z)-2-cyclohexyl-N-hydroxyacetimidoyl chloride. A solution of NCS (2.0 g, 15 mmol),

(EZ)-2-cyclohexylacetaldehyde oxime (1.3 g, 9.2 mmol) and DMF (20 mL) was stirred for 2 hours at 10 °C under N ² . The reaction was treated with water (30ml) and extracted with ethyl acetate (100ml X 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to provide the title compound (300 mg, 19%) as a white solid. 1H NMR (400 MHz, CDCh) 5 8.42 - 8.09 (m, 1H), 2.38 (d, J = 7.2 Hz, 2H), 1.72 (d, J = 11.4 Hz , 5H), 1.35-1.08 (m, 4H), 1.01-0.89 (m, 2H).

[0449] Step C: ( EZ)-N- (( 1 -((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3- b]pyridin-2-yl)methyl)-2-cyclohexyl-N'-hydroxyacetimidamide A solution of 2-((7r,4r)-4-(2-(aminomethyl)imidazo[4,5-d]pyrrolo[ 2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (Intermediate 5, 300 mg, 0.870 mmol), (EZ)-2-cyclohexyl-N-hydroxyacetimidoyl chloride (153 mg, 0.870 mmol), triethylamine (264 mg, 2.61 mmol) and DMF (25 mL) was stirred at room temperature for 2 hours.The same reaction was carried out using 2-((7r,4r)-4-(2-(aminomethyl) imidazo[4,5-a(]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 5, 50 mg, 0.14 mmol), (£Z)-2 chloride -cyclohexyl-N-hydroxyacetimidoyl (25 mg, 0.14 mmol), triethylamine (44 mg, 0.43 mmol), and DMF (2.5 mL) The two reactions were combined and purified by preparative HPLC using a Waters Xbridge Prep OBD C18150 mm x 30 mm, 5 gm column (eluent: 30% to 60% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) for propo Add the title compound (10 mg, 2% yield). MS (ESI): mass calc. for C ²⁵ H ³³ N ⁷ O, 447.27; m/z found, 488.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 11.88 (br s, 1H), 9.16 (br s, 0.7H), 8.73 (s, 0.3H), 8.54 (s, 1H ), 7.47 (br s, 1H), 6.72 (s, 1H), 6.32 -6.17 (m, 0.8H), 5.85 - 5.74 (m, 0.2H) , 4.76 -4.54 (m, 2.5H), 4.47 -4.38 (m, 0.5H), 2.62 - 2.57 (m, 2H), 2.43 - 2, 26 (m, 2H), 2.11-1.87 (m, 7H), 1.73-1.62 (m, 4H), 1.58 1.42 (m, 4H), 1.20-1 0.09 (m, 2H), 0.98-0.87 (m, 2H), 0.83-0.77 (m, 1H).

Reference Example 96 Synthesis and Characterization:

4-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl)benzonitrile

[0450]

[0451 ] Step A: 4-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)benzonitrile. A solution of 2-((7r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1 , 151 mg, 0.344 mmol), 4-formylbenzonitrile (91 mg, 0.69 mmol), and sodium hydrosulfite (192 mg, 0.937 mmol) in DMSO (1 mL), MeOH (1 mL), and distilled water (0.5 ml) in a sealed tube was heated at 100 °C for 16 h. After cooling to room temperature, the reaction was concentrated and the residue was filtered. The yellow solid was washed with water and air dried to give the title compound (150mg), which was used in the following pass without further purification. MS (ESI): mass calc. for C ²⁹ H ²⁴ N ⁶ O ² S, 520.17; m/z found, 521.3 [M+H]+.

[0452] Step B: 4-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- and 1)benzonitrile. The title compound (64 mg, 58% yield) was prepared using analogous conditions to those described in Example 76, Step B using 4-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6 -(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)benzonitrile (150 mg, 0.290 mmol) in place of 4-(4-(1- ((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin-2-yl)piperidin- 1-yl)benzonitrile The title compound was subjected to two columns of flash chromatography The title compound was initially purified using the following conditions: 16 g silica gel column, 3-10% MeOH in DCM. The resulting compound was impure and was subjected to further purification using the following conditions: 16 g silica gel column, 50-100% EtOAc in DCM, MS (ESI): mass calcd for C ²³ H ²⁰ N ⁶ , 380.17, m/z found, 381.1 [M+H] + .1H NMR (400 MHz, CDCl) 5 = 10.02 (br s, 1H), 8.89 (s, 1H), 7, 88 (d, J =8.1Hz, 2H), 7.84-7 .81 (d, J =8.1 Hz, 2H), 7.52 - 7.43 (m, 1H), 6.78 (br s, 1H), 4.49 - 4.39 (m, 1H) , 2.72 - 2.57 (m, 2H), 2.42 (d, J =6.1 Hz, 2H), 2.21 - 2.13 (m, 3H), 2.13 - 2.06 (m, 2H), 1.49-1.31 (m, 2H).

Reference Example 97 Synthesis and Characterization:

4-cyano-W-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydro¡midazo[4,5-a(]pyrrolo[2,3- b]p¡r¡d¡n-2-¡l)met¡l)benzenesulfonam¡da

[0453]

[0454] 4-Cyanobenzenesulfonyl chloride (79.8 mg, 0.396 mmol) was added to a solution of 2- (( 1r,4r)-4- ( 2- (aminomethyl)imidazo[4,5-d] hydrochloride pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 5, 150 mg, 0.396 mmol, 91% purity), triethylamine (0.276 mL, 1.98 mmol), and CH ² Cl ² (5 mL) and stirred for 1 hour at 10 °C. The reaction was diluted with CH ² Cl ^{2 (10} mL), washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC (eluent: CH ² Cl ² :methanol 10:1) to provide the title compound (55 mg, 29% yield) as a white solid. MS (ESI): mass calc. for C ²⁴ H ²³ N ⁷ O ² S, 473.16; m/z found, 474.2 [M+H]+. 1H NMR ((400 MHz, DMSO-ds) ~ 85% major rotamer: 11.92 (s, 1H), 8.75 (br s, 1H), 8.49 (s, 1H), 8.08 - 8.03 (m, 2H), 8.02 - 7.98 (m, 2H), 7.48 (t, J = 2.8 Hz, 1H), 6.74 -6.70 (m, 1H) , 4.62 -4.51 (m, 1H), 4.46 (s, 2H), 2.61 (d, J = 6.0 Hz, 2H), 2.41 - 2.26 (m, 2H), 2.06-1.91 (m, 5H), 1.47-1.32 (m, 2H).

Reference Example 98 Synthesis and Characterization:

2-((1r,4r)-4-(2-(2-(Methylthio)pyrimidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile

[0455]

[0456] A solution of 2-((1fí,4fí)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (intermediate 1.440 mg, 1.00 mmol), 2-(methylthio)pyrimidine-4-carbaldehyde (463 mg, 3.00 mmol), sodium dithionite (523 mg, 3.00 mmol), DMSO (2.5 mL ) and water (0.15 ml) was heated at 100 °C for 3 hours. Water (20 ml) was added, which caused the formation of a precipitate. The precipitate was collected by filtration and purified by flash column chromatography to give the intermediate, 2-((1r,4r)-4-(2-(2-(methylthio)pyrimidin-4-yl)-6-(phenylsulfonyl )imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (400 mg). then dissolved 2-((1r,4r)-4-(2-(2-(methylthio)pyrimidin-4-yl)-6(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile (100mg) in MeOH/THF/NaOH (1M) (3ml/3ml/3ml) and heated at 80°C for 1h. The reaction was concentrated to dryness and partitioned between CH2Cl2 (10 mL) and water (10 mL), collecting the organic phase. The organic layer was concentrated to dryness and purified by flash column chromatography using 10% MeOH in CH ² CL as eluant to provide the title compound (5 mg, 8% yield). MS (ESI): mass calc. for C ²¹ H ²¹ N ⁷ S, 403.16; m/z found, 404.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 10.66 (s, 1H), 8.89 (s, 1H), 8.70 (d, J= 5.1 Hz, 1H), 7.95 (d, J = 5.1 Hz, 1H), 7.47 (dd, J = 3.4, 1.8 Hz, 1H), 6.91 -6.70 (m, 1H), 5.79 (s, 1H ), 2.79 - 2.56 (m, 5H), 2.44 (d, J = 6.4 Hz, 2H), 2.25 - 2.13 (m, 5H), 1.62-1, 35 (m, 2H).

Reference Example 99 Synthesis and Characterization:

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-¿>]pyridin-2-yl)-W- ('(trimethylsilyl)methyl)acetamide

[0457]

[0458] Step A: 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)-N-((trimethylsilyl)methyl)acetamide. The title compound was prepared using analogous conditions to those described in Example 48, step A using (trimethylsilyl)methanamine in place of phenylmethanamine to provide the title compound (84 mg, 75% yield). MS (ESl): mass calc. for C2sH34N6O3SSi, 562.22; m/z found, 563.3 [M+H]+.

[0459] Step B: 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2- yl)-W-((trimethylsilyl)methyl)acetamide. The title compound (26 mg, 41% yield) was prepared as a white solid using analogous conditions to those described in Example 48, step B using 2-(1-((1r,4r)-4-(cyanomethyl) cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-((trimethylsilyl)methyl)acetamide instead of W- benzyl-2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)acetamide. Purification was performed by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl column 100 x 30 mm (eluent: 10-90% CH ³ CN in H ² O, 0.1% TFA). The TFA was removed by dissolving the TFA salt in 10% MeOH in DCM and passing the solution through a 500 mg SILICYCLE SPE-R66030B-03P carbonate column and eluting with 10% MeOH in DCM. MS (ESl): mass calc. for C22H3üN6OSi, 422.23; m/z found, 424.2 [M+H]+. 1H NMR (400 MHz, CDCl3) 5 = 11.22 (br s, 1H), 8.75 (s, 1H), 7.61-7.43 (m, 2H), 6.77-6.71 ( m, 1H), 4.68 (br s, 1H)), 4.01 (d, J =6.6 Hz, 1H), 2.78 (d, J =5.6 Hz, 2H), 2, 55 (br s, 2H), 2.41 (d, J =6.6 Hz, 2H), 2.24-2.11 (m, 2H), 2.14-1.96 (m, 2H), 1.94-1.82 (m, 2H), 1.56-1.41 (m, 2H), 0.00 (s, 9H).

Reference Example 100 Synthesis and Characterization:

2-(( 1r,4r)-4- ( 2- ( 4- ( T rimethylsilyl)cyclohexyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile as its trifluoroacetic acid

[0460]

[0461] Step A: (4-methoxyphenyl)trimethylsilane. To a solution consisting of 4-bromoanisole (9.4 g, 50 mmol) and anhydrous THF (200 mL) at 0 °C, Me3SiCl (12.7 mL, 100 mmol) was added dropwise, followed by n- BuLi (40 mL, 2.5 M in hexanes, 100 mmol). The mixture was stirred at room temperature for 3 hours before quenching with water (150ml) and extracting with ethyl acetate (100ml x 3). The combined organic extracts were washed with brine, dried over Na2SO4. anhydrous, filtered, concentrated under reduced pressure and purified by flash column chromatography (eluent: petroleum ether: ethyl acetate, 20:1) to give the title compound (6.8 g, 69%). 1H NMR (400 MHz, CDCta) 57.49 - 7.44 (m, 2H), 6.95 -6.90 (m, 2H), 3.83 (s, 3H), 0.26 (s, 9H ).

[0462] Step B: 4-(Trimethylsilyl)cyclohexanone. Ammonia (1 L) was condensed in a 3 L 3-necked flask at -78 °C, then a solution of (4-methoxyphenyl)trimethylsilane (45.0 g, 250 mmol) and anhydrous THF (275 mL) was added. , followed by EtOH (200 mL) and sodium (57.5 g, 2.50 mol) portionwise. The resulting mixture was stirred at -40 °C for 2 hours, then treated with EtOH (130 mL). After stirring for 16 hours with gradual warming to room temperature and gradual evaporation of ammonia, the remaining mixture was poured into water (600ml) and extracted with ethyl acetate (600ml x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in EtOH (400 mL) and H ² O (48 mL) and then treated with oxalic acid (6.8 g, 76 mmol). The mixture was stirred at room temperature for 2 hours before it was poured into water (500ml) and extracted with ethyl acetate (500ml x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated to dryness under reduced pressure, and purified by flash column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) to yield the title compound. (18g, 41%). LCMS (ESI): RT = 5.03 min, mass calculated. for CgH ¹ soSI, 170.11; m/z found 171.2 [M+H]+. Reversed phase analytical LC-MS was performed using an Agilent TC-C ¹⁸ column, 50 X 2.1 mm, 5 gm with a flow rate of 0.8 mL/min, eluting with a 0% to 85 gradient. % acetonitrile containing 0.05% TFA (solvent B) and water containing 0.1% TFA (solvent A). The eluent composition was held at 100% A for 1 minute, followed by increasing to 40% B over the course of 4 minutes. The eluent was further increased to 85% B over the course of 2.5 minutes before returning to 100% A over the course of 2 minutes. Total running time was 9.5 minutes. 1H NMR (400 MHz, CDCla) 52.47 - 2.37 (m, 2H), 2.33 - 2.22 (m, 2H), 2.13 - 2.05 (m, 2H), 1.58 -1.43 (m, 2H), 0.97 - 0.87 (m, 1H), 0.00 (s, 9H).

[0463] Step C: (4-(methoxymethylene)cyclohexyl)trimethylsilane. n-Butyllithium (10 mL, 2.5 M in hexane, 25 mmol) was added dropwise to a solution consisting of diisopropylamine (3.5 mL, 25.1 mmol) and anhydrous THF (50 mL) -78° C in N2. After stirring for 30 minutes at 0 °C, to a solution of (methoxymethyl)triphenylphosphonium chloride (8.60 g, 25.1 mmol) and anhydrous THF (50 ml) was added dropwise -78 °C. The mixture was stirred at -78 °C for 10 minutes and then warmed to 0 °C for 30 minutes and then at room temperature for 30 minutes before re-cooling to 0 °C and treating with 4-(trimethylsilyl) solution. )cyclohexanone (2.85 g, 16.7 mmol) and anhydrous THF (20 mL). The mixture was stirred for 2 hours with gradual warming to room temperature before quenching with H ² O (50 mL) and extracting with ethyl acetate (75 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous MgSO4, filtered, concentrated to dryness, and purified by flash column chromatography (eluent: petroleum ether) to give the title compound (3, 00g, 90%). 1H NMR (400 MHz, CDCla) 55.81 (s, 1H), 3.60 (s, 3H), 2.88-2.85 (m, 1H), 2.15-2.12 (m, 1H ), 1.97-1.87 (m, 1H)), 1.87-1.77 (m, 2H), 1.72-1.61 (m, 1H), 1.20-1.10 ( m, 2H), 0.75-0.68 (m, 1H), 0.00 (s, 9H).

[0464] Step D: 4-(Trimethylsilyl)cyclohexanecarbaldehyde. To a solution of (4-(methoxymethylene)cyclohexyl)trimethylsilane (3.0 g, 15 mmol) and THF (100 mL) was added HCbN (35 mL, 70 mmol). After stirring at room temperature for 16 hours, the mixture was quenched with H ² O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, concentrated to dryness under reduced pressure, and purified by flash column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 to 20: 1) to give the title compound (2.3 g, 82%). 1H NMR (400 MHz, CDCh 59.83 (s, 0.3H), 9.68 (s, 0.7H), 2.59-2.53 (m, 0.3H), 2.33-2, 24 (m, 1.2H), 2.14 - 2.06 (m, 1.3H), 1.94-1.91 (m, 1.3H), 1.72-1.59 (m , 1.4H), 1.36 1.15 (m, 3.5H), 0.67 - 0.56 (m, 1H), 0.08 (s, 6.5H), 0, 00 (s, 2.5H).

[0465] Step E: 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-(4-(trimethylsilyl)cyclohexyl)imidazo[4,5-d]pyrrolo[2,3-b] pyridin-1(6H)-yl)cyclohexyl)acetonitrile. The title compound (53 mg, 29%) was prepared from Intermediate 3 (130 mg) using analogous conditions to those found in Example 1, Step A, and using 4-(trimethylsilyl)cyclohexanecarbaldehyde in place of 3-ethoxy. Ethyl -3-iminopropanoate MS (ESI): mass calculated for Ca1HagN5O2SSi, 573.26, m/z found, 574.3 [M+H]+.

[0466] Step F: 2- (( 1r,4r)-4- ( 2- ( 4- ( T rimethylsilyl)cyclohexyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H )-yl)cyclohexyl)acetonitrile as its trifluoroacetic acid salt The title compound (11 mg, 22% yield) was prepared using conditions analogous to those found in Example 197 step B using 2-((1R,4R)- 4-(6-(phenylsulfonyl)-2-(4-(trimethylsilyl)cyclohexyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile instead of 2- (( 1R,4R)-4- ( 2- ( 2- ( 4- methoxypiperidin-1 -yl)-2-oxoethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile). The title compound was subjected to two separate purification methods. It was initially purified by loading a dry solid on flash column chromatography (16 g silica gel column, using 3-10% MeOH in DCM as eluant). Second, the title compound was further purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 10-90% CH3CN in H ² O, 0.1% TFA). MS (ESI): mass calc. for C25H35N5Si, 433.27; m/z found, 434.2 [M+H]+. 1H NMR (400 MHz, CD3OD) = 8.69 (br s, 1H), 7.69 (d, J =3.0 Hz, 1H), 7.00 (d, J =3.5 Hz, 1H ), 4.85 -4.72 (m, 1H), 3.47 (br t, J =11.6 Hz, 1H), 2.70 - 2.58 (m, 2H), 2.53 (d , J =6.1 Hz, 2H), 2.21-2.00 (m, 7H), 2.02-1.88 (m, 2H), 1.78-1.66 (m, 2H), 1.64-1.43 (m, 4H), 0.71 (t, J =12.9 Hz, 1H), 0.00 (s, 9H).

Reference Example 101 Synthesis and Characterization:

( EZ)-N- (( 1- (( 1r,4r)-4- ( cyanomethyl)cyclohexyl)-1 ,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-N'-hydroxy-3,3-dimethylbutanimidamide

[0467]

[0468] Step A: (EZ)-3,3-Dimethylbutanal oxime. It was stirred at room temperature for 24 h. The reaction was concentrated to dryness, the residue diluted with water (40 mL), extracted with ethyl acetate (80 mL X 3), dried over anhydrous Na ² SO ⁴ , filtered, and concentrated to dryness to give the title compound (4.0 g, 70% yield) as a colorless oil. 1H NMR (400 MHz, CDCh) 57.49 (t, J = ^6.8 Hz, ^0.6 H), 6.82 (t, J = ^5.8 Hz, 0.4H), 2.32 (d , J = 5.6 Hz, 0.8H), 2.08 (d, J = ^{6 , 8} Hz, 1.2H), 0.99 (s, 4H), 0.96 (s, 5H).

[0469] Step B: (EZ)-N-hydroxy-3,3-dimethylbutanimidoyl chloride. A solution of NCS (5.80 g, 43.4 mmol),

(EZ)-3,3-dimethylbutanal oxime (2.5 g, 22 mmol) and DMF (15 mL) was stirred for 2 hours at 10 °C under N ² . The reaction was diluted with ethyl acetate (180ml) and washed with water (50ml X 3). The combined organic phases were dried over anhydrous Na ² SO ⁴ , filtered and concentrated to dryness. The residue was purified by flash column chromatography to give the title compound (1.80 g, 55%) as a colorless oil. 1H NMR (400 MHz, CDCh) 58.90 - ^{8 , 6 8} (m, 1H), 2.45 (s, 2H), 1.03 (s, 9H).

[0470] Step C: (£Z)-N-{'(1-((ir,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-c/]pyrrolo[2, 3-b]pyridin-2-yl)methyl)-W'-hydroxy-3,3-dimethylbutanimidamide. A solution of 2-((7r,4r)-4-(2-(aminomethyl)imidazo[4,5-c/]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) hydrochloride acetonitrile (Intermediate 5, 300 mg, 0.87 mmol), (EZ)-N-hydroxy-3,3-dimethylbutanimidoyl chloride (130 mg, 0.87 mmol), triethylamine (264 mg, 2.61 mmol) and DMF (12 mL) was stirred at room temperature for 4 h. The reaction was filtered and the residue was purified by preparative HPLC using a 150 mm x 25 mm Kromasil column, 10 pm (eluent: 28% to 38% (v/v) CH ³ CN and 0.05 H ² O). % NH ³ ) to provide the title compound (99 mg, 27% yield) as a white solid. MS (ESI): mass calc. for C ²³ H ³¹ N ⁷ O, 421.26; m/z found, 422.1 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 11.88 (br s, 1H), 9.26 (s, 0.7H), 8.75 (s, 0.3H), 8.61-8, 46 (m, 1H), 7.47 (br s, 1H), 6.72 (br s, 1H), 6.29 -6.17 (m, 0.7H), 5.63 - 5.51 ( m, 0.3H), 4.71 -4.39 (m, 3H), 2.63 - 2.56 (m, 2H), 2.41 - 2.30 (m, 2H), 2.29 - 2.14 (m, 2H), 2.10-1.88 (m, 5H), 1.57-1.34 (m, 2H), 0.99 (s, 2.4H), 0.94 ( s, ^{6, 6h} ).

Reference Example 102 Synthesis and Characterization:

2-(1-((ir,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-N-( '2-hydroxy-2-phenylethyl)acetamide

[0471]

[0472] To a solution of sodium 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridine -2-yl)acetate (Intermediate 4, ⁶⁶ mg, 0.18 mmol) and 2-amino-1-phenylethanol (51 mg, 0.37 mmol) in ^{dM f} (2 mL) were added PyBOP (190 mg, 0.37 mmol) and DIPEA (0.10 mL, 0.58 mmol) and the reaction mixture was stirred at room temperature for 18 h.The reaction was concentrated to dryness and the residue was purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 10-90% CH ³ CN in H ² O, 0.1% TFA) to give the title compound (17 mg, 16% yield) as a foam. MS (ESI): mass calcd for C ²⁶ H ²⁸ N ⁶ O ² , 456.23, m/z found, 457.4 [M+H]+, 1H NMR (400 MHz, CD ³ OD) 5 = 8 .81 (s, 1H), 7.75 (d, J =3.0 Hz, 1H), ^{7 , 4 4} - ^{7 , 3 4} (m, 5H), 7.09 (d, J =3.5 Hz, 1H), 5.65 (t, J =8.1 Hz, 1H), 4.80 (dd, J =4.5, 7.6 Hz, 1H), 4.67 (br s, 1H) , 4.05 3.95 (m, 1H), 3.58 - 3.38 (m, 3H), 2.55 (d, J =6.1 Hz, 3H), 2.16 - 2.08 (m, 5H) , 1.64-1.40 (m, 2H).

Reference Example 103 Synthesis and Characterization:

(EZ)-W-('(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl) methyl)-W'-hydroxy-2-phenylacetimidamide

[0473]

[0474] Step A: (EZ)-2-phenylacetaldehyde oxime. A mixture of 2-phenylacetaldehyde (5.00 g, 41.6 mmol), hydroxylamine hydrochloride (2.89 g, 41.6 mmol), pyridine (3.29 g, 41.6 mmol) and methanol (50 mL ) was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure, diluted with dichloromethane (200 mL) and washed with aq. HCl (1M, 50ml x 3) and water (100ml x 3). The organic layer was dried over anhydrous Na ² SÜ ⁴ , filtered and concentrated to dryness under reduced pressure. The residue was purified by recrystallization (petroleum ether:ethyl acetate, 10:1) to give the title compound (1.20 g, 21%) as a white solid. 1H NMR (400 MHz, CDCh) 57.97 (s, 1H), 7.37-7.30 (m, 2H), 7.26-7.22 (m, 3H), 6.90 (t, J = 5.3Hz, 1H), 3.75 (d, J = 5.6Hz, 2H).

[0475] Step B: (EZ)-N-hydroxy-2-phenylacetimidoyl chloride. A mixture of NCS (2.37 g, 17.8 mmol),

(EZ)-2-phenylacetaldehyde oxime (1.2 g, 8.9 mmol) and DMF (10 mL) was stirred for 2 hours at 10 °C under N ² . The reaction was diluted with water (20ml) and extracted with ethyl acetate (100ml x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (0-6% ethyl acetate in pet. ether) to provide the title compound (750 mg, 50%) as a white solid. 1H NMR (400 MHz, CDCla) 57.82 (s, 1H), 7.38-7.25 (m, 5H), 3.81 (s, 2H).

[0476] Step C: (EZ)-W-('(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3 -b]pyridin-2-yl)methyl)-W'-hydroxy-2-phenylacetimidamide A solution of 2-((7r,4r)-4-(2-(aminomethyl)imidazo[4,5-c] hydrochloride (]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (Intermediate 5, 300 mg, 0.870 mmol), ('£Z)-W-hydroxy-2-phenylacetimidoyl chloride (148 mg, 0.870 mmol), triethylamine (264 mg, 2.61 mmol) and DMF (25 mL) was stirred at room temperature for 2 hours.The same reaction was carried out using 2-((ir,4r)-hydrochloride 4-(2-(aminomethyl)imidazo[4,5-a(]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 5.50 mg, 0.14 mmol), (EZ)-N-hydroxy-2-phenylacetimidoyl chloride (25 mg, 0.14 mmol), triethylamine (44 mg, 0.43 mmol) and DMF (2.5 mL) The two reactions were combined and purified by HPLC preparative using a Waters Xbridge Prep OBD C ¹⁸ 150 mm x 30 mm, 5 gm column (eluent: 30% to 60% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (64 mg, 15% yield). MS (ESI): mass calc. for C ²⁵ H ²⁷ N ⁷ O, 441.23; m/z found, 442.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 511.87 (br s, 1H), 9.42-9.26 (m, 0.7H), 9.06-8.93 (m, 0.2H) , 8.62 - 8.49 (m, 1H), 7.50 - 7.41 (m, 1H), 7.39 - 7.27 (m, 4H), 7.25 - 7.16 (m, 1H), 6.74 -6.64 (m, 1H), 6.34 -6.26 (m, 0.8H), 6.11 -6.05 (m, 0.3H), 4.57 - 4.41 (m, 3H), 3.65 - 3.55 (m, 2H), 2.61 - 2.57 (m, 2H), 2.39 - 2.16 (m, 1.3H), 2.10-1.77 (m, 5.6H), 1.48-1.37 (m, 1.6H), 1.25-1.14 (m, 0.5H).

Example 104 Synthesis and characterization:

2-(1 -((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl)-W- í4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)acetamide

[0477]

[0478] A solution of sodium 2-(1-((1r,4riM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl) acetate (intermediate 4, 300 mg, 0.835 mmol), 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol hydrochloride (247 mg, 0.835 mmol), DIPEA (216 mg, 1.67 mmol) and DMF (5 mL) was stirred at 0 °C for 1 h, then PyBrOP (467 mg, 1.00 mmol) was added and stirred at room temperature overnight. quenched with 10 mL of water and purified by preparative HPLC using a 150 mm x 20 mm Diamonsil column, 5 pm (eluent: water (0.225% HCO ² H)-28-58% ACN, v/v ) and by preparative TLC (CH ² CL:MeOH = 10:1) to give the title compound (38 mg, 7% yield) as a white solid MS (ESI): mass calcd for C ²⁷ H ²⁴ F ⁶ N ⁶ O ² , 578.19, m/z found, 579.1 [M+H]+ 1H NMR (400 MHz, CD ³ OD): 58.55 (s, 1H), 7.73-7 .66 (m, 4H), 7.49 (d, J = 3.6 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H)), 4.66-4.55 (m , 1H), 4.34 -4.28 (m, 2H ), 2.68-2.49 (m, 4H), 2.21-2.05 (m, 5H), 1.56-1.41 (m, 2H).

Reference Example 105 Synthesis and Characterization:

1-(2-(1-((1r,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl) acetyl)piperidine-4-carbonitrile

[0479]

[0480] The title compound was prepared using analogous conditions to those described in Example 52 using piperidine-4-carbonitrile in place of ( 1S,3R,5R, 7S)-3-aminoadamantan-1-ol hydrochloride to give the title compound (12 mg, 5% yield). This compound was initially purified by preparative acid HPLC using a 150 mm x 30 mm, 5 um Boston Green ODS column (eluent: water (0.05%) HCl-11 to 41% ACN, v/v). This compound was further purified by preparative basic HPLC using a 150 mm x 25 mm DuraShell column, 5 pm (eluent: water (0.05% v/v ammonium hydroxide)-20 to 50% ACN, v/v ). MS (ESI): mass calc. for C ²⁴ H ²⁷ N ⁷ O, 429.23; m/z found, 430.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 5 = 8.82 (s, 1H), 7.75 (d, J =3.5 Hz, 1H), 7.10 (d, J =3.0 Hz, 1H), 4.57 (br s, 1H), 3.99 - 3.86 (m, 2H), 3.68 - 3.58 (m, 1H), 3.53 - 3.43 (m, 1H ), 3.18 - 3.09 (m, 1H), 2.56 (br d, J =6.1 Hz, 4H), 2.24 - 2.06 (m, 7H), 2.05-1 .91 (m, 3H), 1.88-1.74 (m, 1H), 1.62-1.43 (m, 2H).

Reference Example 106 Synthesis and Characterization:

2-(1-((1r,4rj-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-W-(2 ,3-dihydroxypropyl)acetamide

[0481]

[0482] To a solution of sodium 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridine -2-yl)acetate (intermediate 4, 70 mg, 0.20 mmol) and 3-aminopropane-1,2-diol (50 mg, 0.39 mmol) in DMF (2 mL) were added PyBOP (150 mg, 0.30 mmol) and DIPEA (0.10 mL, 0.58 mmol) and stirred at room temperature for 64 h. The reaction was concentrated to dryness and the residue was purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 10 - 90% CH ³ CN in H ² O, 0.1% TFA) to give the title compound (2.0 mg, 2% yield). MS (ESI): mass calc. for C ²¹ H ²⁶ N ⁶ O ³ , 410.21; m/z found, 411.3 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 5 = 8.92-8.74 (m, 1H), 7.80-7.72 (m, 1H), 7.14-7.04 (m, 1H) , 4.69 (br s, 1H), 3.81 - 3.69 (m, 1H), 3.53 (d, J =5.1 Hz, 2H), 3.50 - 3.38 (m, 1H), 2.56 (d, J =6.1 Hz, 5H), 2.25-2.08 (m, 7H), 1.62-1.45 (m, 2H).

Reference Example 107 Synthesis and Characterization:

2-((7r,4r)-4-(2-(2-(4,4-Difluoropiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1(6H)-yl)cyclohexyl)acetonitrile

[0483]

[0484] To a solution of sodium 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b] 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-Acetate pyridin-2-yl) (intermediate 4, 66 mg, 0.18 mmol) and 4,4-difluoropiperidine (58 mg, 0.37 mmol) in DMF (2 mL) were added PyBOP (190 mg, 0.37 mmol ) and DIPEA (0.16 mL, 0.92 mmol) and the reaction mixture was stirred at room temperature for 64 h. The reaction was concentrated to dryness and the residue was purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 10 - 90% CH ³ CN in H ² O, 0.1% TFA) to give the title compound. (24 mg, 24% yield) as a foam. MS (ESI): mass calc. for C ²³ H ²⁶ F ² N ⁶ O, 440.21; m/z found, 441.3 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 5 = 8.82 (s, 1H), 7.74 (d, J =3.5 Hz, 1H), 7.10 (d, J =3.5 Hz, 1H), 4.61 (br s, 1H), 3.80 (td, J =5.8, 18.2 Hz, 4H), 2.56 (d, J =6.1 Hz, 4H), 2 .24-2.10 (m, 8H), 2.10-1.96 (m, 3H), 1.65-1.40 (m, 2H).

Reference Example 108 Synthesis and Characterization:

4-(2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamido )diethyl benzylphosphonate

[0485]

[0486] To a solution of 2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2 -yl)sodium acetate (intermediate 4, 66 mg, 0.18 mmol) and diethyl 4-aminobenzylphosphonate (103 mg, 0.37 mmol) in DMF (2 mL) were added PyBOP (191 mg, 0.367 mmol) and DIPEA (0.10 mL, 0.58 mmol) and the reaction mixture was stirred at room temperature for 64 h. The reaction was concentrated to dryness and the residue was purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 10 - 90% CH ³ CN in H ² O, 0.1% TFA) to give the title compound. (12 mg, 10% yield) as a foam. MS (ESI): mass calc. for C ²⁹ H ³⁵ N ⁶ O ⁴ P, 562.25; m/z found, 563.4 [M+H]+. 1H NMR (400 MHz, CD ³ OD) = 8.81 (s, 1H), 7.74 (d, J =3.5 Hz, 1H), 7.56 (d, J =8.1 Hz, 2H), 7.29 (dd, J =2.3, 8.8 Hz, 2H), 7.10 (d, J =3.5 Hz, 1H), 4.76 (br s, 1H), 4 .07 - 3.96 (m, 4H), 3.24 (s, 1H), 3.19 (s, 1H), 2.62 - 2.46 (m, 5H), 2.26 - 2.09 (m, 6H), 1.59-1.46 (m, 2H), 1.25 (t, J = 7.1 Hz, 6H).

Reference Example 109 Synthesis and Characterization:

Methyl (1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)phenylcarbamate

[0487]

[0488] Step A: (1 -((7r,4r^-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b] pyridin-2-yl)methyl phenylcarbamate A solution of 2-((1r,4r)-4-(2-(hydroxymethyl)-6-(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 7, 100 mg, 0.22 mmol), isocyanatobenzene (53 mg, 0.44 mmol), 3N Et (0.093 mL, 0.67 mmol) and DMF (1 mL) was heated at 60 °C for 40 H. The reaction was only about 50% complete, so more isocyanatobenzene (53 mg, 0.44 mmol) was added and the mixture was heated to 60 °C for 18 h The reaction was concentrated to dryness to provide the title compound (126 mg), which was used in the next reaction without further purification.MS (ESI): mass calcd for C ³⁰ H ²⁸ N ⁶ O ⁴ S, 568.19, m/z found, 569.3 [M+H]+.

[0489] Step B: (1-(( 1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl) methyl phenylcarbamate. A reaction mixture of (1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridine - 2-yl)methyl phenylcarbamate (126 mg, 0.220 mmol), 3 M aq. NaOH (0.27 mL, 0.81 mmol), MeOH (1.5 mL) and THF (1.5 mL) stirred at room temperature for 6h and concentrated. to vacuum. The residue was purified by flash column chromatography (0-10% MeOH in CH ² CL) to give the title compound as a white solid (24 mg, 25% yield). MS (ESI): mass calc. for C ²⁴ H ²⁴ N ⁶ O ² , 428.20; m/z found, 429.2 [M+H]+. 1H NMR (400 MHz, CDCh) = 11.66 (br s, 1H), 8.71 (br s, 1H), 8.47 (br s, 1H), 7.52 (br s, 2H), 7.48 - 7.31 (m, 3H), 7.11 (t, J =7.0 Hz, 1H), 6.60 (br s, 1H), 5.52 (s, 2H), 4, 42 (br s, 1H), 2.44-2.23 (m, 4H), 2.08-1.70 (m, 5H), 1.40-1.22 (m, 2H).

Reference Example 110 Synthesis and Characterization:

( EZ)-N- (( 1- (( 1r,4r)-4- ( Cyanomethyl)cyclohexyl)-1 ,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)-W-hydroxycyclopropanecarboximidamide

[0490]

[0491] ^{Step A: (EZ) - c iclo pro panoca rb oxim id a m id a. A naso lu tio n dec ic lo propanoca rb oxa ld eh id o (3 .00 g , 42 .8 mmol) ,} c lo rh id ra to deh id ro xylam in a (8 .92 g , 128 mmol) , sodium acetate (10.5 g, 128 mmol), ethanol (150 mL) and water (30 mL) were stirred at 70 °C. for 10 h. The reaction was concentrated to dryness, extracted with ethyl acetate (50 mL x 2 ), dried over anhydrous Na2S04, filtered and concentrated to dryness to give the title compound (4.8 g) as a colorless oil. 1H NMR (400 MHz, CDCla): 58.80 (br s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 1.66-1.52 (m, 1H), 0, 69-0.57 (m, 4H).

[0492] Step B: (£Z)-N-hydroxycyclopropanecarbimidoyl chloride. NCS (11 g, 85 mmol) was added to a solution of (£Z)-cyclopropanecarbaldehyde oxime (4.8 g, 56 mmol) and DMF (50 mL) and the reaction mixture was stirred for 2 h at 15 °C. Water (20 ml) was added, the reaction mixture was extracted with ethyl acetate (20 ml), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography to provide the title compound (2.1 g, 28% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.84 (s, 1H), 1.97-1.84 (m, 1H), 1.00-0.93 (m, 2H), 0.89-0 .81 (m, 2H).

[0493] Step C: (£Z)-W-('(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3 -b]pyridin-2-yl)methyl)-W'-hydroxycyclopropanecarboximidamide. A solution of 2-((ir,4r,)-4-(2-(aminomethyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) hydrochloride acetonitrile (Intermediate 5, 300 mg, 0.870 mmol),

(EZ)-W-Hydroxycyclopropanecarbimidoyl chloride (104 mg, 0.870 mmol), triethylamine (0.61 mL, 4.4 mmol) and DMF (5 mL) were stirred for 2 h at 15 °C. Water (10ml) was added and the reaction was extracted with ethyl acetate (20ml) and dichloromethane (10ml X 2). The combined organic extracts were concentrated to dryness and the residue was initially purified by preparative basic HPLC using a Phenomenex Gemini 150 mm x 25 mm, 5 gm column (eluent: 16% to 46% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ). The compound was then further purified by preparative acid HPLC with a Phenomenex Gemini 150 mm x 25 mm, 10 gm column (eluent: 10% to 30% (v/v) CH ³ CN and aqueous HCl (0.006 N) ). Pure fractions from preparative acid HPLC were collected, adjusted to pH = 7-8 with saturated aqueous NaHCO3 and concentrated to dryness. The solid was filtered and washed with water ^(2ml X 3). The filter cake was slurried in water (10 mL) and CH ³ CN (2 mL), the mixture was frozen using dry ice/acetone and then lyophilized to dryness to give the title compound (40 mg, 12% yield). ) as a white mixture. solid. MS (ESI): mass calc. for C ²¹ H ²⁵ N ⁷ O, 391.21; m/z found, 392.0 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 11.87 (br s, 1H), 9.05 (s, 1H), 8.55 (s, 1H), 7.47 (t, J = 3, 2 Hz, 1H), 6.75 -6.68 (m, 1H), 6.33 (t, J = 6.0 Hz, 1H), 4.80 (d, J = 6.0 Hz, 2H ), 4.75 -4.62 (m, 1H), 2.60 (d, J = 5.6 Hz, 2H), 2.42 - 2.27 (m, 2H), 2.06-1, 85 (m, 5H), 1.71-1.61 (m, 1H), 1.57-1.41 (m, 2H), 0.63-0.50 (m, 4H).

Reference Example 111 Synthesis and Characterization:

2-(1-((ir,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin-2-yl)-W- ^pyridin-3-yl)acetamide

[0494]

[0495] To a solution of sodium 2-(1-((7fí,4fí)-4-(c¡anomet¡l)c¡clohex¡l)-1,6-d¡h¡d¡dro¡m¡dazo[ 4,5-a(]pyrrolo[2,3-¿>]p¡r¡d¡n-2-yl)acetate (intermediate 4, 66 mg, 0.18 mmol) and pyridin-3-amine ( 44 mg, 0.47 mmol) in DMF (2 mL) were added PyBOP (190 mg, 0.37 mmol) and DIPEA (0.10 mL, 0.58 mmol) and stirred at room temperature for 18 h. The reaction was concentrated to dryness and the residue was purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 10 - 90% CH ³ CN in H ² O, 0.1% TFA) to give the title compound (14 mg, 14% yield) as a foam MS (ESI): mass calcd for C ²³ H ²³ N ⁷ O, 413.20, m/z found, 414.3 [M+H ]+.1H NMR (400 MHz, CD ³ OD) = 9.38 (s, 1H), 8.86 (s, 1H), 8.63-8.53 (m, 2H), 8.05 ( dd, J=6.1, 8.6Hz, 1H), 7.77 (d, J =3.5Hz, 1H), 7.15 (d, J =3.5Hz, 1H), 4, 97 (s, 2H), 4.77 (br s, 1H), 2.65 - 2.45 (m, 4H), 2.25 (d, J = 10.6 Hz, 2H), 2.20 - 2.08 (m, 3H), 1.62-1.47 (m, 2H).

Reference Example 112 Synthesis and Characterization:

(Z)-W'-('(1-((7r;4r)-4-(C¡anomet¡l)c¡clohex¡l)-1,6-d¡h¡d¡dro¡m¡dazo[4 ,5-a(]pyrrolo[2,3-¿>]p¡r¡d¡n-2-¡l)methoxy¡)-2-cyclopropylacetimidamide, the structure being the (Z) or (E) isomer , and the notation (Z) and its corresponding structure below are chosen arbitrarily.

[0496]

[0497] Step A: (Z)-2-cyclopropyl-N'-hydroxyacetimidamide. A solution of cyclopropylacetonitrile (2.0 g, 25 mmol), hydroxylamine hydrochloride (3.4 g, 49 mmol), Na2CO3 (5.2 g, 49 mmol), ethanol (48 mL), and water (16 mL) was added. stirred for 12 h at 80 °C. The reaction was concentrated to dryness and the residue partitioned between ethyl acetate (50ml) and water (50ml). The organic phase was collected, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to provide the title compound (2.4 g, 77% yield), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-afe): 58.76 (s, 1H), 5.31 (s, 2H), 1.83 (d, J = 7.2 Hz, 2H), 1.00 - 0 .82 (m, 1H), 0.43-0.33 (m, 2H), 0.13-0.05 (m, 2H).

[0498] Step B: (Z)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d] pyrrolo[2,3-b]pyridin-2-yl)methoxy)-2-cyclopropylacetimidamide. A solution of 2-((1r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile (intermediate 8, 300 mg, 0.641 mmol), (Z)-2-cyclopropyl-N'-hydroxyacetimidamide (220 mg, 1.92 mmol), CS ² CO ³ (1.0 g, 3.2 mmol) and DMF (5 mL) was stirred for 18 h at 10 °C. The reaction was concentrated to dryness to provide the title compound (1.6 g, 100% yield), which was used in the next step without further purification. MS (ESI): mass calc. for C ²⁸ H ³¹ N ⁷ O ³ S, 545.22; m/z found, 546.1 [M+H]+.

[0499] Step C: ( Z)-N'- (( 1- (( 1r,4r)-4- ( Cyanomethyl)cyclohexyl)-1 ,6-dihydroimidazo[4,5-d]pyrrolo[2,3- a(]pyridin-2-yl)methoxy)-2-cyclopropylacetimidamide The title compound (60 mg, 23% yield) was prepared using analogous conditions to those described in Example 1, Step B using (Z)-N '-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)-2-cyclopropylacetimidamide (1.6 g, 0.65 mmol, purity 22%) instead of 2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexM)-6-( phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide Purification was initially performed by chromatography on flash column (eluent: DCM:methanol = 100:0 to 85:15).The title compound was further purified by preparative HPLC using a Phenomenex Gemini 150 mm x 25 mm, 10 gm column (eluent: 21% at 51 % (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) MS (ESI): Calcd mass for C ²² H ²⁷ N ⁷ W, 405.23; m/z found, 406.3 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 511.88 (s, 1H), 8.55 (s, 1H), 7.47 (s, 1H), 6.73 (s, 1H), 5.73 (s, 2H), 5.17 (s, 2H), 4.81 - 4.67 (m, 1H), 2.58 (d, J = 5.6 Hz, 2H), 2.43 - 2, 28 (m, 2H), 2.10-1.91 (m, 5H), 1.81 (d, J = 6.4 Hz, 2H), 1.50-1.33 (m, 2H), 0 0.99-0.88 (m, 1H), 0.41-0.32 (m, 2H), 0.11-0.05 (m, 2H).

Reference Example 113 Synthesis and Characterization:

2-((1r,4r)-4-(2-(methoxymethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0500]

[0501] A solution of 2-((1r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-¿>]pyridin-1( 6H)-yl)cyclohexyl)acetonitrile (intermediate 12, 350 mg, 0.750 mmol) in THF (10 mL) was treated with 0.5 M NaOMe in MeOH solution (3.8 mL, 1.9 mmol) at RT for 2 h and concentrated in vacuo. The residue was partitioned between CH ² Cl ² and water. The extract was dried over Na ² SO ⁴ , filtered and concentrated. The residue was purified by flash column chromatography (50-100% EtOAc in heptanes, then 10% MeOH in CH ² Cl ² ), then reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent : 10 - 90% CH ³ CN in H ² O, 0.1% TFA). The collected material was dissolved in 10% MeOH in CH ² Cl ² , passed through two 500 mg SILICYCLE SPE-R66030B-03P carbonates to remove TFA and eluted with 10% MeOH in CH ² Cl ² to give the title compound as a blank compound. solid (98 mg, 41% yield). MS (ESI): mass calc. for C ¹⁸ H ²¹ N ⁵ O, 323.17; m/z found, 324.1 [M+H]+. 1H NMR (400 MHz, CDCh) 513.45 (br s, 1H), 8.71 (s, 1H), 7.56 (d, J =3.5 Hz, 1H), 6.84 (d, J =3.0 Hz, 1H), 4.84 (s, 2H), 4.80 - 4.65 (m, 1H), 3.44 (s, 3H), 2.56 - 2.44 (m, 4H), 2.27-2.14 (m, 3H), 2.17-2.10 (m, 2H), 1.63-1.46 (m, 2H).

Reference Example 114 Synthesis and Characterization:

1-((1r,4rt-4-(Cyanomethyl)cyclohexyl)-N-(2-hydroxyethyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridine-2-carboxamide [ 0502]

[0503] The title compound (21 mg, 28% yield) was prepared using analogous conditions to those described in Example 50, Step A, and using 2-aminoethanol in place of 3-phenylpyrroline-3-ol. MS (ESI): mass calc. for C ¹⁹ H ²² N ⁶ O ² , 366.18; m/z found, 367.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD): 58.64 (s, 1H), 7.51 (d, J = 4.2 Hz, 1H), 6.89 (d, J = 4.1 Hz, 1H ), 5.72 - 5.47 (m, 1H), 3.76 (d, J = 5.3 Hz, 2H), 3.56 (d, J = 5.2 Hz, 2H), 2.74 - 2.46 (m, 4H), 2.26-1.96 (m, 5H), 1.59-1.38 (m, 2H).

Reference Example 115 Synthesis and Characterization:

5-(1-((1r,4r,)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-c/]pyrrolo[2,3-¿>]pyridin-2-yl)picolinonitrile

[0504]

[0505] Step A: 5-(1 -((1r,4r,M-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b ]pyridin-2-yl)picolinonitrile A solution of 2-((1r,4r,M-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino)cyclohexyl)acetonitrile (Intermediate 1, 152 mg, 0.346 mmol), 5-formylpicolinonitrile (92 mg, 0.70 mmol) and sodium hydrosulfite (202 mg, 0.986 mmol) in DMSO (1 mL), MeOH (1 mL ) and distilled water (0.5 mL) in a sealed tube was heated at 100 °C for 16 h. After cooling to room temperature, the reaction was concentrated and the residue filtered. The yellow solid was washed with water and dried. air dried to provide the title compound (150 mg), which was carried on to the next step without further purification MS (ESI): mass calcd for C ²⁸ H ²³ N ⁷ O ² S, 521.16, m/z found, 522.2 [M+H]+.

[0506] Step B: 5-(1 -((7r,4rJ-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )picolinonitrile Mixture of 5-(1 -((1r,4r,M-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b] pyridine-2-yl)picolinonitrile (150 mg, 0.29 mmol), pyrrolidine (0.10 mL, 1.2 mmol), 3 M NaOH (aq) (0.24 mL, 0.72 mmol), THF ( 1.5 mL) and MeOH (1.5 mL) was stirred at room temperature for 5 h and concentrated in vacuo The residue was purified by flash column chromatography (3-10% MeOH in CH ² Cl ² ) to give title compound as an off-white solid (8.0 mg, 7% yield) MS (ESI): mass calcd for C ²² H ¹⁹ N ⁷ , 381.17, m/z found, 382.2 [M +H]+.1H NMR (400MHz, CDCla) 5 = 10.13 (br s, 1H), 9.02 (d, J =1.5 Hz, 1H), 8.91 (s, 1H), 8 .23 (dd, J =2.0, 8.1 Hz, 1H), 7.93 (d, J =8.1 Hz, 1H), 7.49 (t, J =3.0 Hz, 1H) , 6.79 (dd, J =2.0, 3.0 Hz, 1H), 4.46 -4.37 (m, 1H), 2.73 - 2.59 (m, 2H), 2.42 (d, J =6.1Hz, 2H), 2.25 - 2.15 (m, 2H), 2.15 - 2.03 (m, 3H), 1.40 (dq, J =3.5, 13.0 Hz, 2H)

Example 116 Synthesis and characterization:

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-hydroxy-3-methylbutanamide

[0507]

[0508] HATU (100 mg, 0.264 mmol) was added to a solution of 2-((7r,4rM-(2-(aminomethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine hydrochloride -1(6H)-yl)cyclohexyl)acetonitrile (intermediate 5, 100 mg, 0.264 mmol, 91% pure), beta-hydroxyisovaleric acid (31.2 mg, 0.264 mmol), DIEA (0.230 mL, 1.32 mmol), and CH ² Cl ² (5 mL) and stirred for 0.5 h at 10 C. The reaction was diluted with CH ² Cl ² (10 mL), washed with water (10 mL), dried over anhydrous Na2S04, filtered. and concentrated to dryness.The residue was initially purified by preparative TLC (eluent: CH ² Cl ² :methanol = 10:1).The residue was then further purified by preparative HPLC using an Agela DuraShell 150 mm x 25 column. mm, 5 gm (eluent: 8% to 38% (v/v) CH ³ CN and H ² O with 10 mM NH ⁴ HCO ³ ) to give the title compound (30 mg, 28% yield) ^. S(ESI): mass calcd for C ²² H ²⁸ N ⁶ O ² , 408.23, m/z found, 409.2 [M+H]+ 1H NMR (400 MHz, DMSO-ds): 511, 89 (s, 1H), 8.53 (s , 1H), 8.52 - 8.47 (m, 1H), 7.48 (t, J = 2.8 Hz, 1H), 6.72 (s, 1H), 4.87 (s, 1H) , 4.69 (d, J = 5.2 Hz, 2H), 4.61 - 4.47 (m, 1H), 2.59 (d, J = 6.0 Hz, 2H), 2.42 - 2.32 (m, 2H), 2.30 (s, 2H), 2.10-1.86 (m, 5H), 1.48-1.31 (m, 2H), 1.19 (s, 6H).

Reference Example 117 Synthesis and Characterization:

1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-N-(2-hydroxy-2-methylpropyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-carboxamide

[0509]

[0510] The title compound (27 mg, 34% yield) was prepared using analogous conditions to those described in Example 50, Step A, using 1-amino-2-methylpropane-2-ol in place of 3-phenylpyrroline -3-ol. MS (ESI): mass calc. for C ²¹ H ²⁶ N ⁶ O ² , 394.21; m/z found, 395.2 [M+H]+. 1H NMR (500 MHz, CDCh): 10.79 (s, 1H), 8.82 (s, 1H), 8.24 (d, J =4.0 Hz, 1H), 7.55-7, 37 (m, 1H), 6.89 -6.65 (m, 1H), 6.30 - 5.56 (m, 1H), 3.52 (d, J = 6.5 Hz, 2H), 3 .10 (s, 1H), 2.63 -2.53 (m, 2H), 2.39 (d, J = 6.5 Hz, 2H), 2.25-1.96 (m, 5H), 1.64-1.43 (m, 2H), 1.36 (s, 6H).

Reference Example 118 Synthesis and Characterization:

2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( pyridin-4-yl)acetamide

[0511]

[0512] To a solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)acetate (intermediate 4, 66 mg, 0.18 mmol) and pyridin-4-amine (41 mg, 0.44 mmol) in DMF (2 mL) were added PyBOP (190 mg, 0.37 mmol) and DIPEA (0.10 mL, 0.58 mmol) and stirred at room temperature for 18 h. The reaction was concentrated to dryness and the residue was purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 X 30 mm column (eluent: 10-90% CH ³ CN in H ² O, 0.1% TFA ) to provide the title compound (6 mg, 6% yield) as a foam. MS (ESI): mass calc. for C ²³ H ²³ N ⁷ O, 413.20; m/z found, 414.3 [M+H]+.

1H NMR (400 MHz, CD ³ OD) = 8.86 (s, 1H), 8.66 (d, J = 7.6 Hz, 2H), 8.19 (d, J = 7.1 Hz, 2H), 7.77 (d, J =3.5 Hz, 1H), 7.17 (d, J =3.5 Hz, 1H), 4.73 (br s, 1H), 2.65 - 2 .47 (m, 4H), 2.30-2.20 (m, 3H), 2.19-2.08 (m, 4H), 1.63-1.42 (m, 2H).

Reference Example 119 Synthesis and Characterization:

2-((7r,4r)-4-(2-(Thiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0513]

[0514] Step A: 2-((7r,4r)-4-(6-(phenylsulfonyl)-2-(thiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1(6H)-yl)cyclohexyl)acetonitrile. To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino)cyclohexyl)acetonitrile (Intermediate 1, 197 mg, 0.448 mmol) and thiazole-5-carboxaldehyde (120 mg, 1.00 mmol) as solids. DMSO (2ml), MeOH (2ml) and distilled water (1ml) were added resulting in a yellow mixture. Sodium hydrosulfite (262 mg, 1.51 mmol) was then added as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100 °C for 1 h. The reaction was cooled to room temperature and added dropwise to 60 mL of water with stirring. The precipitate that formed was collected by filtration and dried first in open air and then under high vacuum for 3 h to give the title compound (176 mg, 78% yield) as a canary yellow solid, which was used in the next step without further purification. MS (ESI): mass calc. for C ²⁵ H ²² N ⁶ O ² S ² , 502.12; m/z found, 503.1 [M+H]+.

[0515] Step B: 2-((7r,4r)-4-(2-(Thiazol-5-yl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile. The title compound (68 mg, 54% yield) was prepared using analogous conditions to those described in Example 2, Step B using 2-((1r,4r)-4-(6-(Phenylsulfonyl)-2-( thiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (176 mg, 0.35 mmol) in place of 2- ( 1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin-2-yl)- N-(2-hydroxy-2-methylpropyl)acetamide The residue was purified by flash column chromatography (40 g SiO ² , 0-5% 2N NH3-MeOH/EA) to give the title compound MS ( ESI): mass calcd for C ¹⁹ H ¹⁸ N ⁶ S, 362.13, m/z found, 363.1 [M+H]+ 1H NMR (500 MHz, DMSO-ds): 5 12.04 ( s, 1H), 9.36 (s, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 7.55 (t, J = 3.1 Hz), 1H), 6 .80 (dd, J = 3.5, 1.8 Hz, 1H), 4.74 -4.54 (m, 1H), 2.57 (d, J = 6.3 Hz, 2H), 2, 49-2.40 (m, 2H), 2.12-1.94 (m, 5H), 1.49-1.34 (m, 2H).

Example 120 Synthesis and characterization:

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-d¡h¡d¡dro¡m¡dazo[4,5-a(]p¡rrolo[2,3-b ]p¡r¡d¡n-2-¡l)-N-(2-methox¡et¡l)acetam¡da

[0516]

[0517] ^{Step A: 2 - (1 - ( (1 r ,4 r ) -4 - (cyanomethyl) cyclohex yl) -6 - ( phenyl sulfonyl) -1 ,6 -d ih id ro im id azo [4 ,5 -d ]p ir ro lo [2 ,3 -b ]p ir id in -2 - il) -N - (2 -me to x ie til) ace ta m} Going . M ezc la de 2-(1 -((1 r ,4 r ) -4 -(c ia nome ti l) c ic lo hex il) -6 -( fen ils ulfo n il) -1 ,6 - dih id ro im id azo [4 ,5 -d ]p ir ro lo [2 ,3 -b ]p ir id in -2 - il )ace ta to deet ilo ( in te rm ed io 3, 160 mg , 0.32 mmol), 2-me to xie ta nam in a (210 mg, 2.8 mmol) and NH ⁴ NO ³ (50 mg, 0.63 mmol) was heated at 65 °C for 16 h. After standing at room temperature overnight, CH ² Cl ² and water were added to the mixture. The precipitated white solid was filtered, washed with water, and dried to give the title compound (69 mg, 41%). The filtrate was extracted with CH ² Cl ² , the combined extracts washed with water and the aqueous phase re-extracted with CH ² Cl ² (x 1). The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide the second portion of the title compound (90 mg, 53%) as an off-white solid. MS (ESI): mass calc. for C ²⁷ H ³⁰ N ⁶ O ⁴ S, 534.6; m/z found, 535.2 [M+H]+. 1H NMR (400 MHz, CDCh) = 8.84 (s, 1H), 8.23 (d, J = 7.6 Hz, 2H), 7.85 (d, J = 4.0 Hz, 1H) , 7.60 - 7.54 (m, 1H), 7.52 - 7.45 (m, 2H), 6.85 (d, J =4.0 Hz, 2H), 4.63 -4.52 (m, 1H), 3.96 (s, 2H), 3.42 (d, J =2.5 Hz, 4H), 3.29 (s, 3H), 2.42 (d, J =6, 1 Hz, 2H), 2.38-2.25 (m, 2H), 2.16 (d, J =13.1 Hz, 2H), 2.10-1.96 (m, 3H), 1, 54-1.40 (m, 2H).

[0518] Step B. 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)-N-(2-methoxyethyl)acetamide. The title compound was prepared using analogous conditions to those described in Example 1, Step B using 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl)acetamide (90 mg, 0.17 mmol) and 3N NaOH (aq) in place of 2 -(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-c/|pyrrolo[2,3-b]pyridin-2- yl)-N-(2-hydroxy-2-methylpropyl)acetamide and KOH in water to provide the title compound as a white solid (50 mg, 75% yield). MS (ESI): mass calc. for C ²¹ H ²⁶ N ⁶ O ² , 394.21; m/z found, 395.2 [M+H]+. 1H NMR (400 MHz, CDCla) = 11.38 (br s, 1H), 8.75 (s, 1H), 7.69 (br s, 1H), 7.47 (t, J = 3.0 Hz, 1H), 6.77 - 6.70 (m, 1H), 4.67 (br s, 1H), 4.07 (s, 2H), 3.51 - 3.45 (m, 4H), 3.31 (s, 3H), 2.56 (br s, 2H), 2.42 (d, J = 6.6 Hz, 2H), 2.19 (br d, J = 12.6 Hz, 2H ), 2.15-2.02 (m, 3H), 1.57-1.41 (m, 2H).

Reference Example 121 Synthesis and Characterization:

2-((1r,4r)-4-(2-(4-(4-(Hydroxymethyl)benzoyl)phenyl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin-1(6H) -yl)cyclohexyl)acetonitrile

[0519]

[0520] Step A: 2-((1r,4r)-4-(2-(4-(4-(Hydroxymethyl)benzoyl)phenyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile. To a solution of 2-(( 7r,4r^-4-((5-nitro-1 -(phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile ( To intermediate 1.294 mg, 0.670 mmol) in DMSO (5.70 mL) and MeOH (1.14 mL) in microwaveable vial was added 4-(4-(hydroxymethyl)benzoyl)benzaldehyde (177 mg, 0.737 mmol) , followed by sodium hydrosulfite (343 mg, 1.67 mmol).The vial was stoppered and heated at 100 °C over the weekend.After cooling to room temperature, the reaction was diluted with water (5 mL) and stirred for 5 minutes.The tan precipitate that formed was collected by filtration, washed with water (50 mL) and allowed to dry completely.The solid was eluted from the Büchner funnel using CH ² Cl ² /MeOH and collected in a round bottom flask.The organic phase was then concentrated to dryness to provide the title compound as a tan solid (421 mg, 99%), which was used without further purification.MS (ESI): mass calc for C ³⁶ H ³¹ N ⁵ O ⁴ S, 629.21;m/z enc ontrated, 630.3 [M+H]+

[0521] Step B: 2-((1r,4r)-4-(2-(4-(4-(Hydroxymethyl)benzoyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1(6H)-yl)cyclohexyl)acetonitrile. The title compound (136 mg, 41% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2-((1r,4r)-4-(2-(4-(4-( Hydroxymethyl)benzoyl)phenyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (421 mg, 0.669 mmol) in place of 2- ( 1- (( 1r,4r)-4- (Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b|pyridin-2- M)-N-(2-hydroxy-2-methylpropyl)acetamide to provide the title compound. The crude material was purified on a 24 gram silica gel column using 0-10% MeOH in DCM as eluent. To further purify the title compound, it was triturated with acetonitrile and collected by vacuum filtration to provide the title material as a white solid. MS (ESI): mass calc. for C ³⁰ H ²⁷ N ⁵ O ² , 489.22; m/z found, 490.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.03 (s, 1H), 8.68 (s, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.90 ( d, J = 7.9 Hz, 2H)), 7.81 (d, J = 7.8 Hz, 2H), 7.58 - 7.49 (m, 3H), 6.82 (d, J = 3.6 Hz, 1H), 5.44 (t, J = 5.7 Hz, 1H), 4.64 (d, J = 5.8 Hz, 2H), 4.53 -4.39 (m, 1H), 2.54 (d, J = 6.7 Hz, 2H), 2.47-2.38 (m, 2H), 2.11-1.92 (m, 5H), 1.37-1 .21 (m, 2H).

Reference Example 122 Synthesis and Characterization:

1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-W-(bxetan-3-yl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin- 2-carboxamide

[0522]

[0523] The title compound (25 mg, 24% yield) was prepared using analogous conditions to those described in Example 50, and using oxetan-3-amine in place of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²⁰ H ²² N ⁶ O ² , 378.18; m/z found, 379.2 [M+H]+. 1H NMR (500 MHz, CDCla) d 10.25 (s, 1H), 8.85 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.46 (dd, J = 3.6, 1.8 Hz, 1H), 6.88 -6.74 (br, 1H), 6.32 - 5.64 (m, 1H), 5.41 - 5.16 (m, 1H ), 5.03 (t, J = 7.2 Hz, 2H), 4.76 (dd, J = 7.0, 6.3 Hz), 2H), 2.76 - 2.51 (m, 2H ), 2.40 (d, J = 6.6 Hz, 2H), 2.22-2.02 (m, 5H), 1.57-1.38 (m, 2H).

Reference Example 123 Synthesis and Characterization:

2- (( 1r,4r)-4- ( 2- ( 1H -pyrazol-4-yl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile

[0524]

[0525] Step A: 2-(( 1r,4r)-4-(6-(phenylsulfonyl)-2-(1H-pyrazol-4-yl)imidazo[4,5-a(|pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 1070 mg, 2.44 mmol) and 1H-pyrazole-4-carbaldehyde (444 mg, 4.62 mmol ) as solids. DMSO (12 mL), MeOH (12 mL) and distilled water (6 mL) were added to the reaction mixture resulting in a yellow mixture. Then sodium hydrosulfite (1060 mg, 6, 09 mmol) as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100 °C for 3 h. The reaction was cooled to room temperature and added dropwise to 60 mL of water with stirring. and stirring continued for 30 minutes.The white precipitate that formed was collected by filtration, washed with water (50 mL) and dried first in the open air and then under high vacuum overnight. . A portion of the material (208 mg) was purified by flash column chromatography (24 g SO ² , 0-15% 2N NH3-MeOH/EA) to provide the title compound (112 mg, 9% yield) as a solid. white. MS (ESI): mass calc. for C ²⁵ H ²³ N ⁷ O ² S, 485.16; m/z found, 486.2 [M+H]+.

[0526] Step B: 2- (( 1r,4r)-4- ( 2- ( 1 H-pyrazol-4-yl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile To a 10 mL microwave vial was added 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-(1H-pyrazol-4-yl) imidazo[4,5-a(|pyrrolo[2,3-¿>]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (110 mg, 0.227 mmol) as a solid followed by the addition of tetrabutylammonium fluoride (0.566 ml, 1 M, 0.566 mmol) and the vial was sealed and heated at 100 °C in a microwave for 30 min. The reaction was purified by flash column chromatography to give the title compound (56 mg, 71% yield) as a white powder MS (ESI): mass calcd for C ¹⁹ H ¹⁹ N ⁷ , 345.17, m/z found, 346.1 [M+H]+ 1H NMR (500 MHz, D ^m SO- ds): 513.38 (s, 1H), 11.89 (s, 1H), 8.57 (s, 1H), 8.43 - 7.81 (m, 2H), 7.49 (t, J = 3.0 Hz, 1H), 6.75 (dd, J = 3.5, 1.8 Hz, 1H), 4.67 -4.46 (m, 1H), 2.56 (d, J = 6.3 Hz, 2H), 2.49-2.39 (m, 2H), 2.13-1.91 (m, 5H), 1.45-1.30 (m, 2H).

Reference Example 124 Synthesis and Characterization:

(Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)benzimidamide; the structure being the (Z) or (E) isomer, and the (Z) notation and its corresponding structure below are chosen arbitrarily

[0527]

[0528] Step A: 2-(( 1r,4r)-4-(2-((((Z*)-2-Amino-2-phenylvinyl)oxy)methyl)-6-(phenylsulfonyl)imidazo[4, 5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile 2,2,2-trifluoroacetate. A mixture of 2-((1r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile (intermediate 13, 49 mg, 0.10 mmol), N'-hydroxybenzimidamide (29 mg, 0.21 mmol), K ² CO ³ (23 mg, 0.17 mmol) in DMF (1 mL) stirred at room temperature for 15 hours. Additional W-hydroxybenzimidamide (16 mg, 0.12 mmol), K ² CO ³ (45 mg, 0.33 mmol) and DMF (1 mL) were added. After stirring overnight, the solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC (10-90% CH ³ CN in H ² O, 0.1% TFA) to give the title compound (50 mg, 70%), MS (ESI): mass calc. for C ³⁰ H ²⁹ N ⁷ O ³ S, 567.2; m/z found, 568.3 [M+H]+.

[0529] Step B: (Z*)-N'-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)methoxy)benzimidamide. A mixture of 2-((1r,4r)-4-(2-((((Z)-2-amino-2-phenylvinyl)oxy)methyl)-6-(phenylsulfonyl)imidazo[4,5-d] Pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile-2,2,2-trifluoroacetate (50 mg, 0.073 mmol), 1 M NaOH (aq) (0.25 mL, 0. 25 mmol), THF (0.7 mL) and MeOH (0.7 mL) was stirred at RT for 18 h and concentrated in vacuo. The residue was purified by reverse phase HPLC (10-90% CH ³ CN in H ² O, 0.1% TFA). The fractions were collected and the solvents were removed under reduced pressure. The residue was partitioned between saturated NaHCO3 (aq) and EtOAc (x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound as an off-white solid (30 mg, 95%). MS (ESI): mass calc. for C ²⁴ H ²⁵ N ⁷ O, 427.21; m/z found, 428.3 [M+H]+. 1H NMR (400 MHz, CDCh) 5 = 10.92 (br s, 1H), 8.84 (br s, 1H), 7.67-7.57 (m, 2H), 7.46-7.36 (m, 4H), 6.72 (d, J =2.0 Hz, 1H), 4.94 -4.79 (m, 3H), 2.65 - 2.45 (m, 2H), 2, 37 (d, J =6.6 Hz, 2H), 2.21-1.98 (m, 5H), 1.51-1.34 (m, 2H).

Reference Example 125 Synthesis and Characterization:

( EZ)-N- (( 1- (( 1r,4r)-4- ( Cyanomethyl)cyclohexyl)-1 ,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin-2- yl)methyl)-W'-hydroxy-3-methoxypropanimidamide

[0530]

[0531] A solution of 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin-1(6H)-yl hydrochloride )cyclohexyl)acetonitrile (intermediate 5, 300 mg, 0.870 mmol), N-hydroxy-3-methoxypropanimidoyl chloride (120 mg, 0.870 mmol), triethylamine (0.364 mL, 2.61 mmol) and DMF (6 mL) were stirred. for 2 h at 20 ° C. The reaction mixture was concentrated to dryness and purified by preparative HPLC using a 150 mm x 30 mm Boston Green ODS column, 5 pm (eluent: 4% to 34% (v/v) of CH ³ CN and H ² O with 0.1% TFA) The pure fractions from this HPLC run were collected, adjusted to pH = 7-8 with saturated aqueous NaHCO3 and volatile solvents removed under reduced pressure. was extracted with ethyl acetate (20 mL X 2).The combined organic extracts were dried over Na2SO4, filtered, and concentrated to dryness.The residue was further purified by preparative HPLC with a 150 mm X 25 mm Kromasil column, 10 pm (eluent: 8% to 38% (v/v) d e CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (30 mg, 8% yield) as a white solid. MS (ESI): mass calc. for C ²¹ H ²⁷ N ⁷ O ² , 409.22; m/z found, 410.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 11.88 (s, 1H), 9.21 (s, 1H), 8.56 (s, 1H), 7.49-7.45 (m, 1H ), 6.74 -6.69 (m, 1H)), 6.33 (t, J = 5.6 Hz, 1H), 4.72 - 4.60 (m, 3H), 3.43 (t , J = 7.2 Hz, 2H), 3.19 (s, 3H), 2.60 (d, J = 6.0 Hz), 2H), 2.43 - 2.24 (m, 2H), 2.11-1.84 (m, 7H), 1.57-1.43 (m, 2H).

Re fere n ce e xample 126 S in te sis an d charac ter iza tio n:

2-((ir,4rt-4-(2-(((4-(4-Ethynylbenzoyl)benzyl)oxy)methyl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile

[0532]

[0533] Step A: (4-(Bromomethyl)phenyl)(4-bromophenyl)methanone. To a solution of 4-bromo-4'-methylbenzophenone (1.00 g, 3.64 mmol) in acetonitrile (5 mL) under nitrogen was added NBS (0.712 g, 4.00 mmol) and AIBN (0.060 mg, 0.36 mmol) and stirred for 2 h at 90 °C to give a white solution. The reaction was concentrated to dryness and the residue was purified by flash column chromatography to provide the title compound (1.3 g, 83% yield) as a white solid. 1H NMR (400MHz, CDCl): 57.76 (d, J = 7.6 Hz, 2H), 7.69-7.60 (m, 4H), 7.51 (d, J = 8.0 Hz, 2H), 4.53 (s, 2H).

[0534] Step B: 2-((1r,4r)-4-(2-(((4-(4-Bromobenzoyl)benzyl)oxy)methyl)-6-(phenylsulfonyl)imidazo[4,5-d] pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile. A solution of 2-((ir,4r,)-4-(2-(hydroxymethyl)-6-(phenylsulfonyl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin-1(6H) -yl)cyclohexyl)acetonitrile (Intermediate 7, 500 mg, 0.80 mmol), (4-(bromomethyl)phenyl)(4-bromophenyl)methanone (515 mg, 1.20 mmol), silver oxide (742 mg, 3.20 mmol) and DMF (12 mL) was stirred at room temperature for 18 h in the dark.The reaction was filtered through a pad of diatomaceous earth and concentrated to dryness, which was purified by flash column chromatography. to give the title compound as a yellow solid MS (ESI): mass calcd for C37H32BrN5Ü4S, 721.14, m/z found, 723.9 [M+H]+ 1H NMR (400 MHz, CDCl3): 58.90 (s, 1H), 8.25 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 4 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.66 - 7.63 (m, 4H), 7.58 - 7.55 (m, 1H), 7.51 -7.47 (m, 2H), 7.43 - 7, 40 (m, 2H), 6.84 (d, J=4.0 Hz, 1H), 4.93 (s, 2H), 4.65 -4.59 (m, 3H), 2.44 - 2 .41 (m, 2H), 2.38-2.30 (m, 2H), 2.15-2.07 (m, 5H), 1.51-1.43 (m, 2H).

[0535] Step C: 2-((ir,4rt-4-(6-(phenylsulfonyl)-2-(((4-(4-((trimethylsilyl)ethynyl)benzoyl)benzyl)oxy)methyl)imidazo[4 ,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile 2-((1 r,4r)-4-(2-(((4-(4-Bromobenzoyl )benzyl)oxy)methyl)-6-(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (40 mg, 0.037 mmol), Pd (PPh3)4 (4.2 mg, 0.0037 mmol), triethylamine (45 mg, 0.44 mmol), copper(I) iodide (0.42 mg, 0.0022 mmol), and DMF (1 mL) were were added to a 2 mL microwave tube and purged with nitrogen for 10 minutes.The reaction was treated with trimethylsilylacetylene (36 mg, 0.37 mmol) and stirred while heating at 110 °C in a microwave for 1 hour before Cool to room temperature.The suspension was filtered through a pad of Celite® and the pad was washed with ethyl acetate (10 mL).The filtrate was concentrated to dryness and purified by preparative HPLC using a Phenomenex Synergi C column. ¹⁸ x 150mm x 30mm, 4mm (eluent: 77% to 95% (v/v) of CH ³ CN and aqueous HCl (0.006 N)). The pure fractions were collected, the pH adjusted to pH = 7-8 with solid sodium bicarbonate and the volatiles removed in vacuo. The residue was diluted with water (15 mL) and extracted with CH ² CL (45 mL X 3), and the combined organic extracts dried over anhydrous Na2SO4, filtered, and concentrated to dryness to provide the title compound as a solid. yellow. MS (ESI): mass calc. for C ⁴² H ⁴¹ NsO4SSi, 739.26; m/z found, 740.2 [M+H]+.

[0536] Step D: 2-(( 1r,4r)-4-(2-(((4-(4-Ethynylbenzoyl)benzyl)oxy)methyl)imidazo[4,5-d]pyrrolo[2,3- b]pyridine-1(6H)-yl)cyclohexyl)acetonitrile. The title compound (a light yellow solid, 800 mg, 8% yield)) was prepared using analogous conditions to those described in Example 1, Step B using 2-((1r,4r)-4-(6-( phenylsulfonyl)-2-(((4-(4-((trimethylsilyl)ethynyl)benzoyl)benzyl)oxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile (16 mg, 0.018 mmol) in place of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5 -d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. MS (ESI): mass calc. for C ³³ H ²⁹ N ⁵ O ² , 527.23; m/z found, 528.0 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 511.93 (br s, 1H), 8.58 (s, 1H), 7.77-7.72 (m, 3H), 7.71 (s, 1H ), 7.67 - 7.63 (m, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.51 - 7.48 (m, 1H), 6.76 -6, 72 (m, 1H), 4.96 (s, 2H), 4.69 (s, 2H), 4.66 -4.58 (m, 1H), 4.49 (s, 1H), 2.58 (d, J = 6.0 Hz, 2H), 2.43-2.29 (m, 2H), 2.06-1.88 (m, 5H), 1.45-1.33 (m, 2H ).

Reference Example 127 Synthesis and Characterization:

2-((1r,4r)-4-(2-(2-((fi)-3-Hydroxypyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b ]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0537]

[0538] A solution of sodium 2-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)acetate (Intermediate 4, 300 mg, 0.835 mmol), (R)-pyrrolidin-3-ol (114 mg, 0.918 mmol), DiPeA (0.29 mL, 1.67 mmol) and DMF (5 mL) were PyBOP (428 mg, 0.918 mmol) was added at 0 °C and stirred at room temperature for 3 h. The mixture was quenched with 10 mL of water and extracted with EtOAc (3 x 20 mL). aqueous phase were concentrated to provide a residue which was initially purified by preparative HPLC using a Xtimate C18150 3 25 mm X 5 pm column (eluent: 13% to 33% (v/v) CH ³ CN and H ² O with NH ⁴ 10 mM HCO ³ ) The resulting compound was then washed with 2-methoxy-2-methylpropane/methanol for further purification to provide the title compound (79 mg, 23% yield) as a white solid MS ( ESI): mass calcd for C ²² H ²⁶ N ⁶ O ² , 406.21, m/z found, 407.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6): 511.82 (br s, 1H), 8.49 (s, 1H), 7.47 - 7.44 (m, 1H), 6.72 -6.69 (m, 1H), 5.15 -4 .98 (m, 1H), 4.47 -4.25 (m, 2H), 4.23 -4.07 (m, 2H), 3.77 - 3.62 (m, 2H), 3.51 - 3.42 (m, 1H), 3.33 -3.25 (m, 1H), 2.59 - 2.54 (m, 2H), 2.41 - 2.27 (m, 2H), 2 0.08-1.73 (m, 7H), 1.44-1.28 (m, 2H).

Reference Example 128 Synthesis and Characterization:

Ethyl 3-(1-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)azetidine -1-carboxylate

[0539]

[0540] Step A: 2-((1 r,4r)-4-((1 -((4-Bromophenyl)sulfonyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine-4- yl)amino)cyclohexyl)acetonitrile. 2-((7r,4rM-aminocyclohexyl)acetonitrile hydrochloride mixture (Intermediate 1, Step D, 437 mg, 2.50 mmol), 1-((4-bromophenyl)sulfonyl)-4-chloro-5-nitro -1 H-pyrrolo[2,3-b]pyridine (932 mg, 2.24 mmol), DIEPA (1.30 mL, 7.94 mmol) in DmSo (3 mL) was heated at 100 °C for 1 h The mixture was cooled H ² O (100 mL) was added Solids formed After filtration the solids were collected, redissolved in CH ² Cl ² (50 mL) and washed with H ² O (50 mL) The organic layer was concentrated to give the title compound (1100 mg, 95% yield) which was used without further purification MS (ESI): mass calcd for C21H2üBrN5O4S, 518.4 m/z found , 517.7/519.7 (Cl atom) [M+H]+.

[0541] Step B: 2-((7r,4r,M-(2-(Azetidin-3-yl)-6-((4-bromophenyl)sulfonyl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile A solution of 2-((7r,4r,M-((1-((4-bromophenyl)sulfonyl)-5-nitro-1H-pyrrolo[ 2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (519 mg, 1.00 mmol), tert-butyl 3-formylazetidine-1-carboxylate (371 mg, 2.00 mmol), tert-butyl dithionite sodium (523 mg, 3.00 mmol), dMsO (2.5 mL), and water (0.15 mL)) was heated at 100 °C for 16 hours. Water (20 mL) was added. The precipitate that formed was collected by filtration and purified by flash column chromatography.To this material was added CH ² Cl ² (5 mL) and TFA (1 mL) and stirred for 0.5 h.The reaction was concentrated to dryness To the residue was added CH ² Cl ² (10 mL) and saturated NaHCO3 (10 mL), the organic layer was collected and concentrated to dryness to give the crude title compound (200 mg) MS (ESI): mass Calcd for C25H25BrN6O2S, 552.09, m/z found, 554.7 [M+H]+.

Step C: 3-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)azetidine-1- ethyl carboxylate To a solution of ethyl carbonochloridate (0.0362 mL, 0.379 mmol) and triethylamine (40 mg, 0.40 mmol) in CH ² Cl ² (3 mL) was added 2-((ir,4r ,)-4-(2-(azetidin-3-yl)-6-((4-bromophenyl)sulfonyl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile (200 mg, 0.361 mmol) in CH ² Cl ² (0.5 mL) and stirred at room temperature for 16 h Water (10 mL) was added, the organic layer collected and concentrated to dryness The residue was dissolved in THF/MeOH/NaOH (1 M) (1 mL/1 mL/1 mL) and heated at 80 °C for 1 hour The reaction was concentrated to dryness and the residue was purified by chromatography on flash column to give title compound (16 mg, 11% yield) MS (ESI): mass calcd for C ²² H ²⁶ N ⁶ O ² , 406.21, m/z found, 407.2 [ M+H]+.1H NMR (400 MHz, CDCh): 58.69 (s, 1 ^h ), 7.40 (d, J = 3.5 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H), 4.70 -4.35 (m, 4H), 4.26 -4 .01 (m, 3H), 3.88-3.42 (m, 1H), 2.68 - 2.40 (m, 4H), 2.29-1.92 (m, 5H), 1.59 -1.38 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

Reference Example 129 Synthesis and Characterization:

2-((1r,4r)-4-(2-((3-Isopropyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)imidazo[4,5-d]pyrrolo [2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0542]

[0543] A solution of ( EZ)-N- (( 1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b ]pyridin-2-yl)methyl)-N'-hydroxyisobutyrimidamide (15 mg, 0.035 mmol), as prepared in Example 61, stirred CDI (6.2 mg, 0.038 mmol) and THF (1 mL) for 1 .5 h at 70 °C. The reaction was concentrated to dryness and the residue was purified by preparative HPLC using a Phenomenex Gemini 150 mm x 25 mm column, 10 pm (eluent: 25% to 55% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (5 mg, 35% yield) as a white solid. MS (ESI): mass calc. for C ²² H ²⁵ N ⁷ O ² , 419.21; m/z found, 420.1 [M+H]+. 1H NMR (400 mHz, DMSO-affe): 11.93 (s, 1H), 8.54 (s, 1H), 7.53 - 7.47 (m, 1H), 6.75 (s, 1H), 5.39 (s, 2H), 4.64 -4.49 (m, 1H), 3.09 - 2.97 (m, 1H), 2.61 (d, J = 6.0 Hz , 2H), 2.44-2.26 (m, 2H), 2.12-1.91 (m, 5H), 1.55-1.37 (m, 2H), 1.15 (d, J = 6.8Hz, 6H).

Reference Example 130 Synthesis and Characterization:

2-((1r,4r)-4-(2-((4-(4-Ethynylbenzoyl)phenoxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile

[0544]

[0545] Step A: 2-((1r,4r)-4-(2-((4-(4-Bromobenzoyl)phenoxy)methyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile. A solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (289 mg, 0.968 mmol), 2- (( 1r,4r)-4- ( 2- (chloromethyl)-6-(phenylsulfonyl)imidazo[4,5 -d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (Intermediate 8, 530 mg, 1.02 mmol), DMF (10 mL), K ² CO ³ (282 mg, 2.04 mmol) and KI (16.9 mg, 0.102 mmol) was stirred at 60 °C for 3 h. The reaction was quenched with water (250ml) and washed with EtOAc (2 x 250ml), the organic extracts combined, washed with brine (150ml), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by flash column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 to 36:64) to give the title compound (330 mg, 44% yield) as a yellow solid. MS (ESI): mass calc. for C36H30BrN5O4S, 707.12; m/z found, 710.0 [M+H]+.

[0546] Step B: 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-((4-(4-((trimethylsilyl)ethynyl)benzoyl)phenoxy)methyl)imidazo[4,5 -d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile. 2-((lr,4r)-4-(2-((4-(4-Bromobenzoyl)phenoxy)methyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1(6H)-yl)cyclohexyl)acetonitrile (250 mg, 0.353 mmol), Pd(PPh3) 4 (40.8 mg, 0.0353 mmol), triethylamine (428 mg, 4.23 mmol), copper iodide (I) (4.0 mg, 0.0.021 mmol) and DMF (6 mL) were added to a 10 mL microwave tube and purged with nitrogen for 10 minutes. The reaction was treated with trimethylsilylacetylene (347 mg, 3.53 mmol) and stirred while heating at 110 °C in a microwave for 1 hour before cooling to room temperature. The suspension was filtered through a pad of Celite® and the pad was washed with ethyl acetate (20 ml). filtering concentrated to dryness and purified by flash column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 1:2) to give the title compound as a yellow solid (212 mg, ⁶⁸ %). MS (ESI): mass calc. for C ⁴¹ H ³⁹ N ⁵ O ⁴ SSL 725.25; m/z found, 726.2 [M+H]+. 1H NMR (400 MHz, CDCh): 58.91 (s, 1H), 8.28-8.20 (m, 2H), 7.86 (d, J =4.0 Hz, 1H), 7.76 (d, J = ^{8 , 8} Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.58 - 7.46 (m, 5H), 7.12 (d, J = ^{8 , 8} Hz, 2H), 6.83 (d, J = 4.0 Hz, 1H), 5.51 (s, 2H), 4.73 -4.59 (m, 1H), 2.44 ( d, J = 6.0 Hz, 2H), 2.40-2.28 (m, 2H), 2.22-2.12 (m, 2H), 2.11-1.93 (m, 3H) , 1.54-1.46 (m, 2H), 0.27 (s, 9H).

[0547] Step C: 2-(( 7r,4r)-4-(2-((4-(4-Ethynylbenzoyl)phenoxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1 ( ⁶ H)-yl)cyclohexyl)acetonitrile. The title compound (a light yellow solid, (42 mg, 27% yield)) was prepared using analogous conditions to those described in Example 1, Step B using 2-((1r,4r)-4-(6- (phenylsulfonyl)-2-((4-(4-((trimethylsilyl)ethynyl)benzoyl)phenoxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile (90 mg, 0.12 mmol) in place of 2-('7-('('7r,4r)-4-phcyanomethyl)c¡clohex¡l)-6-(phenylsulfon¡ l)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. Purification was performed by preparative HPLC using a Phenomenex Gemini 150 mm x 25 mm, 10 gm column (eluent: 45% to 75% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ). MS (ESI): mass calc. for C ³² H ²⁷ N ⁵ O ² , 513.22; m/z found, 514.0 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 11.98 (br s, 1H), 8.62 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.71 - 7.67 (m, 2H), 7.66 - 7.62 (m, 2H), 7.53 - 7.49 (m, 1H), 7.30 (d, J = 8.8 Hz, 2H ), 6.79 -6.73 (m, 1H), 5.67 (s, 2H), 4.70 -4.57 (m, 1H), 4.46 (s, 1H), 2.59 ( d, J = 6.0 Hz, 2H), 2.44-2.28 (m, 2H), 2.07-1.94 (m, 5H), 1.49-1.31 (m, 2H) .

Reference Example 131 Synthesis and Characterization:

2-(1-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (4-(hydroxymethyl)bicyclo[2,2,1]heptan-1-yl)acetamide

[0548]

[0549] To a solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)acetate (intermediate 4, 200 mg crude, 0.557 mmol), (4-aminobicyclo[2.2.1]heptan-1-yl)methanol hydrochloride (109 mg, 0.612 mmol) and DIPEA (0.291 mL, 1.67 mmol) in dry DMF (6 mL), PyBrOP (285 mg, 0.612 mmol) was added at 0 °C and stirred at room temperature for 15 hours. The mixture was diluted with water (10ml) and extracted with ethyl acetate (20ml X 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC using a 3.25 mm DuraShell 150 column, 3.5 mm (eluent: 12% to 42% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (37.2 mg, 14% yield) as a yellow solid. MS (ESI): mass calc. for C ²⁶ H ³² N ⁶ O ² , 460.26; m/z found, 461.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD): 58.53 (s, 1H), 7.48 (d, J = 4.0 Hz, 1H), 6.84 (d, J = 4.0 Hz, 1H ), 4.04 (s, 2H), 3.56 (s, 2H), 2.66 - 2.51 (m, 4H), 2.18 - 2.05 (m, 5H), 2.00- 1.82 (m, 5H), 1.77-1.65 (m, 4H), 1.57-1.47 (m, 2H)), 1.44-1.35 (m, 2H).

Example 132 Synthesis and characterization:

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-8-fluoro-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide

[0550]

[0551] 2-(1-((7r,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N -(2-hydroxy-2-methylpropyl)acetamide (55.4 mg, 0.136 mmol), as prepared in Example 1, added to a 2 dram vial, then dissolved in CH ³ CN (1 mL) and water (1 mL).NaHCO3 (34 mg, 0.41 mmol) was added with vigorous stirring.The reaction was slowly treated with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,bis(tetrafluoroborate) 2.2]octane (Selectfluoro®) (72.1 mg, 0.203 mmol) as a solution in 1 mL of CH ³ CN The reaction mixture was stirred at room temperature and monitored by LCMS The reaction was extracted with ( 2 x 10 mL) CH ² Cl ² .The combined organic layers were dried over anhydrous MgSO4 and concentrated to dryness.The residue was initially purified by reverse phase acidic HPLC using a 50 mm x 250 mm Xbridge column, 10 pm (10-70% CH ³ CN -water with TFA as eluent) The resulting compound was subjected to medium further purification Basic reverse phase HPLC using a 50 mm x 100 mm Xbridge column, 5 pm (CH 3 CN-water with NH ⁴ OH as eluent) to give the title compound (4 mg, 7% yield) as a white solid. MS (ESI): mass calc. for C ²² H ²⁷ FN ⁶ O ² , 426.22; m/z found, 427.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 511.74 (s, 1H), 8.52 (s, 1H), 8.23-8.00 (m, 1H), 7.49 (s, 1H) , 4.50 (s, 2H), 4.07 (s, 2H), 3.08 (d, J = 5.9 Hz, 2H), 2.58 - 2.54 (m, 2H), 2, 35 (d, J = 14.8 Hz, 2H), 2.00-1.80 (m, 5H), 1.33 (d, J = 12.7 Hz, 2H), 1.09 (s, 6H ).

Reference Example 133 Synthesis and Characterization:

1-((7r,4r1-4-(cyanomethyl)cyclohexyl)-N-methyl-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridine-2-carboxamide

[0552]

[0553] The title compound (28 mg, 41% yield) was prepared using analogous conditions to those described in Example 50, Step A using methylamine in place of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ¹⁸ H ²⁰ N ⁶ O, 336.17; m/z found, 337.2 [M+H]+. 1H NMR (500 MHz, CDCla): 11.28 (s, 1H), 8.83 (s, 1H), 7.90 (d, J = 5.1 Hz, 1H), 7.62 -7, 41 (m, 1H), 6.93 -6.75 (m, 1H), 6.31 - 5.76 (br, 1H), 3.06 (d, J = 5.1 Hz, 3H), 2 .75 - 2.55 (m, 2H), 2.40 (d, J = 6.6 Hz, 2H), 2.27 - 2.03 (m, 5H), 1.60-1.40 (m , 2H).

Example 134 Synthesis and characterization:

2-(( 7r,4r^-4-(2-(1 -(Methylsulfonyl)azetidin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyr'idin-1 (6Hj- yl)cyclohexyl)acetonitrile

[0554]

[0555] To a solution of 2-((7r,4rM-(2-(azetidin-3-yl)-6-((4-bromophenyl)sulfonyl)imidazo[4,5-d]pyrrolo[2,3- b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (50.0 mg, 0.0900 mmol), as prepared in Example 128, Step B, and DIPEA (3equiv.) in CH ² Cl ² (5 ml) methanesulfonyl chloride (10.3 mg, 0.0903 mmol) in THF (0.5 ml) was added and stirred at room temperature for 1 h Water (20 ml) was added, the organic phase was collected and was concentrated to dryness. The residue was dissolved in THF/MeOH/NaOH (1 M) (1 mL/1 mL/1 mL) and the mixture was heated at 80 °C for 1 h. The reaction was concentrated to dryness and the residue was purified by flash column chromatography to give the title compound (7.00 mg, 19% yield) MS (ESI): mass calcd for C ²⁰ H ²⁴ N ⁶ O ² S, 412.17, m /z found, 413.2 [M+H]+.1H NMR (500 MHz, CDCla): 59.22 (s, 1H), 8.79 (s, 1H), 7.43-7.34 (m , 1H), 6.77 -6.57 (m, 1H), 4.65 -4.37 (m, 4H), 4.26 -4.06 (m, 1H), 3.49 (d, J = 5.1Hz, 1H), 2.98 (s, 3H); 2.72-2.36 (m, 4H), 2.27-1.91 (m, 5H), 1.49-1.37 (m, 2H).

Reference Example 135 Synthesis and Characterization:

2-(1 -((7r,4rM-(cyanomethyl)c¡clohex¡l)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)-N- ((1S,4S)-4-(trimethylsilyl)cyclohexyl)acetamide

[0556]

[0557] Step A: (4-methoxyphenyl)trimethylsilane. To a solution of 4-bromoanisole (50.0 g, 267 mmol) in dry THF (1000 mL) at 0 °C was added Me 3 SiCl (68.0 mL, 535 mmol) followed by n-BuLi (2, 50 M in hexanes, 200 mL, 0.500 mol). The reaction mixture was stirred at room temperature for 3 hours. Water (500ml) was added, the layers separated and the aqueous layer extracted with ethyl acetate (400ml X 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give the title compound (45.0 g, 69% yield).

1H NMR (400 MHz, CDCla): 57.51 - 7.44 (m, 2H), 6.97 -6.90 (m, 2H), 3.84 (s, 3H), 0.27 (s, 9H).

[0558] Step B: 4-(Trimethylsilyl)cyclohexanone. Ammonia (700 mL) was condensed in a 2 L three-necked flask at -78 °C. (4-Methoxyphenyl)trimethylsilane (27.0 g, 150 mmol) in anhydrous THF (165 mL) was added, followed by EtOH (120 mL) and sodium (34.5 g, 1.50 mol) in portions and stirred. at -40 °C for 2 hours. EtOH (80 mL) was added and the ammonia was gradually evaporated overnight at room temperature. Water (600ml) was added to the reaction and extracted with ethyl acetate (600ml X 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was dissolved in EtOH (300 mL) and water (36 mL) and oxalic acid (4.10 g, 46.0 mmol) was added and stirred at room temperature for 2 hours. Water (500ml) was added and the reaction was extracted with ethyl acetate (500ml X 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluent: petroleum: ethyl acetate = 15:1) to give the title compound (11.0 g, 43% yield) as a light yellow sticky compound. 1H NMR (400MHz, CDCh): 52.46 - 2.38 (m, 2H), 2.34 - 2.23 (m, 2H), 2.13 - 2.04 (m, 2H), 1.57 -1.44 (m, 2H), 0.98 - 0.87 (m, 1H), 0.00 (s, 9H).

[0559] Step C: 4-(trimethylsilyl)cyclohexanone oxime. 4-(Trimethylsilyl)cyclohexanone (4.0 g, 23 mmol), hydroxylamine hydrochloride (3.3 g, 47 mmol), C^COO Na (4.0 g, 49 mmol), and ethanol (100 mL) were added. ) to a 250 mL round bottom container. flask and stirred at room temperature for 16 hours. The mixture was diluted with water (50ml), extracted with ethyl acetate (100ml X 3), the combined organic extracts washed with brine (100ml), dried over anhydrous Na2SO4, filtered and concentrated to dryness. to provide the title compound (4.0 g, 92%) as a light yellow solid. 1H R ^m N (400MHz, CDCta): 53.44-3.33 (m, 1H), 2.49-2.37 (m, 1H), 2.14-1.99 (m, 2H), 1 .97-1.86 (m, 2H), 1.76-1.62 (m, 1H), 1.39-1.18 (m, 2H), 0.81-0.69 (m, 1H) , -0.03 (s, 9H).

[0560] Step D: 4-(Trimethylsilyl)cyclohexanamine. 4-(Trimethylsilyl)cyclohexanone oxime (4.0 g, 0.77 mmol), Raney Ni (100 mg) and MeOH/NH4OH (4:1) (75 mL) were added to a 100 mL round bottom flask. and stirred. at room temperature under H ² atmosphere for 16 hours. The mixture was filtered through a pad of diatomaceous earth and the filtrate concentrated to dryness to provide the title compound (3.0 g, 81% yield) as a colorless oil. MS (ESI): mass calc. for CgH ²¹ NSi, 171.14; m/z found, 172.2 [M+H]+.

[0561] Step E: benzyl ((1S,4S)-4-(trimethylsilyl)cyclohexyl)carbamate. 4-(Trimethylsilyl)cyclohexanamine (500 mg, 2.92 mmol), Na2CO3 (928 mg, 8.76 mmol) and THF (30 mL) were added to a 100 mL round bottom flask and stirred at 0 °C. for 10 minutes. CbzCl (1.50 g, 8.80 mmol) was added at 0 °C and stirred at room temperature for 4 hours. The reaction was combined with two other reactions and the resulting mixture was poured into water (100 mL), extracted with CH ² CI ² (100 mL X 4). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (petroleum ether : ethyl acetate = 15:1 to 6:1) to give the title compound as a diastereomeric mixture (500 mg, 56% yield). The diastereomeric mixture was separated by supercritical fluid chromatography (ChiralPak AD, Daicel Chemical Industries, Ltd, 250 X 30 mm, 5 |um; Mobile phase: A: supercritical CO 2 , B: ethanol (0.1% NH ³ .H ² O), A:B = 75:25 at 60 mL/min, column temperature: 38 °C, nozzle pressure: 100 bar, nozzle temperature: 60 °C, evaporator temperature: 20 °C ; trimmer temperature: 25 °C; wavelength: 220 New Mexico). The pure fractions were collected and concentrated to dryness. The residue was dissolved in ethyl acetate (5ml), washed with water (2ml) and concentrated to dryness. The residue was partitioned between CH ³ CN (1 mL) and water (5 mL) and lyophilized to dryness to give the title compound as the (1S,4S) analog (190 mg, 21% yield). MS (ESI): mass calc. for C17H27NO2Si, 305.18; m/z found, 306.0 [M+H]+. 1H NMR (400MHz, CDCh): 57.43-7.30 (m, 5H), 5.17-5.07 (m, 2H), 4.94 (br s, 1H), 3.99-3, 88 (m, 1H), 1.83-1.74 (m, 2H), 1.60-1.50 (m, 4H), 1.30-1.16 (m, 2H), 0.64 - 0.53 (m, 1H), -0.04 (s, 9H). The diastereoisomer (1r,4r)-4-(trimethylsilyl)cyclohexanamine was also isolated (280 mg, 31% yield). MS (ESI): mass calc. for C^Ha/NOaSi, 305.18; m/z found, 306.0 [M+H]+. 1H NMR (400MHz, CDCls) 7.41 - 7.29 (m, 5H), 5.09 (s, 2H), 4.57 (br. s., 1H), 3.43 (br. s., 1H), 2.11 - 2.02 (m, 2H), 1.80-1.71 (m, 2H), 1.26-1.12 (m, 2H), 1.10 - 0.98 ( m, 2H), 0.47-0.37 (m, 1H), -0.05 (s, 9H).

[0562] Step F: ( 1S, 4S)-4-(Trimethylsilyl)cyclohexanamine. Benzyl (1S, 4 s)-4-(trimethylsilyl)cyclohexyl)carbamate (370 mg, 1.21 mmol), 10 wt% Pd/C (wet) (100 mg) and MeOH (30 mL) were added. a 250 mL round bottom flask. The reaction was stirred at room temperature under H ² for 6 hours. The mixture was filtered through a pad of diatomaceous earth and the filtrate concentrated to dryness to provide the title compound (177 mg, 85.0% yield) as a sticky gray compound. MS (ESI): mass calc. for C9H21NSi, 171.14; m/z found, 172.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD): 53.04-2.98 (m, 1H), 1.62-1.54 (m, 4H), 1.52-1.44 (m, 4H), 0.65 - 0.55 (m, 1H), -0.02 - -0.06 (m, 9H).

[0563] Step G: 2-(1-((1r,4r,)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin- 2-yl)-N-((1S, 4S)-4- (trimethylsilyl)cyclohexyl)acetamide To a solution of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6 Sodium -dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 4, 60 mg, 0.17 mmol) and (1S,4S)-4-(trimethylsilyl) cyclohexanamine (43 mg, 0.25 mmol) in DMF 3 mL)) PyBOP (170 mg, 0.33 mmol) and DIPEA (0.10 mL, 0.58 mmol) and the reaction stirred at room temperature for 18 h. After removing the DMF in vacuo, water was added to the residue and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over anhydrous MgSO ⁴ , filtered, and concentrated to dryness. The residue was purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 X 30 mm column (eluent: 10-90% CH ³ CN in H ² O, 0.1% TFA) to provide the title compound ( 26 mg, 26% yield). MS (ESI): mass calc. for C27H3sN6OSi, 490.29; m/z found, 491.4 [M+H]+. 1H NMR (400 MHz, CD ³ OD) = 8.80 (s, 1H), 7.73 (d, J =3.5 Hz, 1H), 7.08 (d, J =2.5 Hz, 1H), 4.93 (s, 2H), 4.66 (br s, 1H), 4.04 (br s, 1H), 2.55 (br d, J =5.6 Hz, 4H), 2 .25 - 2.08 (m, 5H), 1.82 (br d, J =10.1 Hz, 2H), 1.66-1.43 (m, 8H), 0.66 (br t, J = 10.9Hz, 1H), 0.00 (s, 9H).

Reference Example 136 Synthesis and Characterization:

1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-W-('(1-hydroxycycloheptyl)methyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-carboxamide

[0564]

[0565] The title compound (61 mg, 70% yield) was prepared using analogous conditions to those described in Example 50, Step A using 1-(aminomethyl)cycloheptanol instead. of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²⁵ H ³² N ⁶ O ² , 448.26; m/z found, 449.3 [M+H]+. 1H NMR (500 MHz, CDCla): 512.29 (s, 1H), 8.78 (s, 1H), 8.40-8.15 (m, 1H), 7.55 (d, J =3, 4 Hz, 1H), 6.83 (d, J = 3.4 Hz, 1H), 6.30 - 5.33 (m, 2H), 3.69 - 3.40 (m, 2H) 2.62 - 2.21 (m, 4H), 2.16-1.87 (m, 5H), 1.81-1.33 (m, 14H).

Reference Example 137 Synthesis and Characterization:

Is obu til ((1 -( ( 1 r ,4 r ) -4 -(C ianomethyl ) c ic lo hex yl) -1 ,6 -d ¡h ¡dro ¡m ¡midazo [4 ,5 - a ( ]p ¡r ro Io [2 ,3 -b ]p ¡r ¡d ¡n -2 -¡ I)met¡I)ca rb ama to

[0566]

[0567] Step A: Methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate. A solution of methyl 1H-pyrazole-4-carboxylate (500 mg, 3.97 mmol) and dry THF (10 mL) was added to a 0 °C (ice/water) suspension of sodium hydride in mineral oil. (317 mg, 60% purity, 7.93 mmol) and dry THF (10 mL) and stirred for 1 h with gradual warming to 10 °C. The reaction was then treated with a solution of SEM-Cl (793 mg, 4.76 mmol) and dry THF (5 mL) at 0 °C and stirred overnight at 10 °C. The reaction was quenched with saturated aqueous NH4Cl (20 mL) and concentrated to dryness. The aqueous phase was extracted with ethyl acetate (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (gradient eluent: petroleum ether: ethyl acetate = 100:0 to 85:15) to give the title compound (400 mg, 39% yield) as a colorless oil. MS (ESI): mass calc. for CnH20N2O3Si, 256.12; m/z found, 256.9 [M+H]+. 1H NMR (400 MHz, CDCh): 5 8.06 (s, 1H), 7.94 (s, 1H), 5.43 (s, 2H), 3.84 (s, 3H), 3.57 ( t, J = 8.0 Hz, 2H), 0.91 (t, J = 8.0 Hz, 2H), -0.02 (s, 9H).

[0568] Step B: 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylic acid. NaOH solution (109 mg, 2.73 mmol) and water (1 mL) were added to a solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (350 mg, 1.37 mmol), MeOH (1 mL) and THF (1 mL) and stirred for 2.5 h at 20 °C. The reaction was concentrated to dryness, diluted with water (5 mL) and adjusted to pH=2-3 with 1M HCl. The precipitate that formed was filtered, washed with water (3ml x 2) and dried under high vacuum to provide the title compound (300mg, 86% yield) as a white solid. MS (ESI): mass calc. for C1üH18N2O3Si, 242.11; m/z found, 243.0 [M+H]+.

[0569] Step C: (carbonic isobutyl) 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylic anhydride. Isobutyl chloroformate (186 mg, 1.08 mmol) was added to a 0 °C solution (ice/water) of 1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazole-4-carboxylic acid (250 mg, 0.897 mmol), 4-methylmorpholine (136 mg, 1.35 mmol) and dry THF (5 mL) and stirred for 1 hour at 10 °C. The reaction was concentrated to dryness and the residue partitioned between water (10 mL) and CH ² Cl ² (20 mL). The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to provide the title compound (370 mg, 102% yield) as a light yellow oil. MS (ESI): mass calc. for C15H26N2O5Si, 342.16; m/z found, 342.9 [M+H]+. 1H NMR (400 MHz, CDCla): 58.17 (s, 1H), 8.02 (s, 1H), 5.45 (s, 2H), 4.10 (d, J = 6.8 Hz, 2H ), 3.60 (t, J = 8.4 Hz, 2H), 2.12 - 2.01 (m, 1H), 1.00 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 8.4 Hz, 2H), 0.01 - -0.06 (m, 9H).

[0570] Step D: Isobutyl ((1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- and 1)methyl)carbamate. A solution of 2-((7r,4r)-4-(2-(Aminomethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1( 6H) -yl)cyclohexyl)acetonitrile hydrochloride (Intermediate 5, 170 mg, 0.493 mmol), (carbonic isobutyl) 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylic anhydride (199 mg, 0.493 mmol), 4-methylmorpholine (150 mg, 1.48 mmol) and THF (5 mL) was stirred for 18 h at 25 °C. The reaction was concentrated to dryness, dissolved in CH ² Cl ² (20 mL), the organic phase washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC using an Agela DuraShell 150 mm x 25 mm column, 5 pm (eluent: 32% to 62% (v/v) CH ³ CN and H ² O with 10 mM NH ⁴ HCO ³ ) to provide the title compound (55 mg, 27% yield) as a white solid. MS (ESI): mass calc. for C ²² H ²⁸ N ⁶ O ² , 408.23; m/z found, 409.3 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 11.88 (s, 1H), 8.53 (s, 1H), 7.84 (s, 1H), 7.47 (s, 1H), 6, 71 (s, 1H), 4.73 -4.42 (m, 3H), 3.92 - 3.66 (m, 2H), 2.67 - 2.57 (m, 2H), 2.43 - 2.23 (m, 2H), 2.19-1.65 (m, 6H), 1.54-1.29 (m, 2H)), 1.12-0.63 (m, 6H).

Reference Example 138 Synthesis and Characterization:

N-(2-cyanoethyl)-1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide

[0571]

[0572] The title compound (10 mg, 43% yield) was prepared using analogous conditions to those described in Example 50, Step A, using 3-aminopropanenitrile in place of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²⁰ H ²¹ N ⁷ O, 375.18; m/z found, 376.2 [M+H]+. 1H NMR (500 MHz, CDCls): 10.36 (s, 1H), 8.82 (s, 1H), 8.27 (t, J = 6.4 Hz, 1H), 7.47 (t, J = 2.9 Hz, 1H), 6.94 -6.70 (m, 1H), 6.32 - 5.70 (m, 1H), 3.77 (q, J = 6.6 Hz, 2H ), 2.79 (t, J = 6.6 Hz, 2H), 2.70 -2.55 (m, 2H), 2.42 (d, J = 6.6 Hz, 2H), 2.24 - 2.03 (m, 5H), 1.57-1.43 (m, 2H).

Reference Example 139 Synthesis and Characterization:

N-((1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin-2-yl)methyl) cyclohexanecarboxamide

[0573]

[0574] Cyclohexanecarbonyl chloride (58.0 mg, 0.396 mmol) was added dropwise to a solution of 2-((7r,4r)-4-(2-(aminomethyl)imidazo[4,5-a] hydrochloride (|pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 5, 150 mg, 0.396 mmol), triethylamine (0.276 mL, 1.98 mmol) and CH ² Cl ² (5 mL) and stirred for 1 hour at 10 C. The reaction was diluted with CH ² Cl ² (10 mL), washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC (eluent: CH ² CL:methanol = 10:1) to give the title compound (70 mg, 42% yield) as a white solid MS (ESI): mass calcd for C ²⁴ H ³⁰ N ⁶ O, 418.25, m/z found, 419.3 [M+H]+.

1H NMR (400 MHz, CDCla): 510.54 (s, 1H), 8.76 (s, 1H), 7.45 (t, J = 2.4 Hz, 1H), 6.88 (br s, 1H), 6.73 (s, 1H), 4.82 (d, J = 4.8 Hz, 2H), 4.73 -4.59 (m, 1H), 2.63 - 2.45 (m , 2H), 2.41 (d, J = 6.8 Hz, 2H), 2.28-2.13 (m, 3H), 2.12-1.95 (m, 3H), 1.94 1 .74 (m, 5H), 1.57-1.38 (m, 4H), 1.36-1.18 (m, 3H).

Reference Example 140 Synthesis and Characterization:

2-(( 7r,4r^-4-(2-(3-Cyclopropyl-4,5-dihydro-1,2,4-oxadiazol-5-yl)imidazo[4,5-a(|pyrrolo[2, 3-b]pyridin-1 ( 6H)- yl)cyclohexyl)acetonitrile

[0575]

[0576] 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) hydrochloride acetonitrile (intermediate 5, 200 mg, 0.580 mmol), N-hydroxycyclopropanecarbimidoyl chloride (139 mg, 0.580 mmol), triethylamine (0.40 mL, 2.9 mmol), and DMF (5 mL) were stirred for 2 h at 20° C. The reaction was concentrated to dryness and the residue was partitioned between water (5ml) and ethyl acetate (10ml) The organic phase was collected, dried over anhydrous Na2SO4, filtered and dried. concentrated to dryness. The residue was initially purified by preparative HPLC using a 150 mm x 25 mm Phenomenex Gemini column, 5 pm (eluent: 18% to 48% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ). The residue was then further purified by preparative HPLC using a 150 mm x 25 mm Phenomenex Gemini column, 10 pm (eluent: 18% to 48% (v/v) CH ³ CN and 0.05 H ² O). % NH ³ ) to provide the title compound (8 mg, 3% yield) as a white solid. MS (ESI): mass calc. for C ²¹ H ²³ N ⁷ O, 389.20; m/z found, 390.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 511.99 (s, 1H), 8.61 (s, 1H), 7.76 (s, 1H), 7.54-7.48 (m, 1H) , 6.76 (s, 1H), 6.73 (s, 1H), 4.63 -4.51 (m, 1H), 2.60 (d, J = 5.6 Hz, 2H), 2, 43 - 2.31 (m, 2H), 2.13-1.86 (m, 5H), 1.79-1.68 (m, 1H), 1.42-1.26 (m, 2H), 0.99-0.79 (m, 4H).

Reference Example 141 Synthesis and Characterization:

W-('(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-bjpyridin-2-yl)methyl)cyclohexanesulfonamide

[0577]

[0578] Cyclohexanesulfonyl chloride (482 mg, purity 15%, 0.396 mmol) was added dropwise to a solution of 2-((fr,4r)-4-(2-(aminomethyl)imidazo[4,5] hydrochloride -a(|pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 5, 150 mg, 0.396 mmol), triethylamine (0.276 mL, 1.98 mmol) and CH ² Cl ² (5 mL) and stirred for 1 hour at 10 C. The reaction was diluted with CH ² Cl ² (10 mL), washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to The residue was purified by flash column chromatography and by preparative HPLC twice using a Phenomenex Gemini 150 mm x 25 mm column, 5 pm (eluent: 30% to 60% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (5 mg, 3% yield) as a white solid MS (ESI): mass calcd for C ²³ H ³⁰ N ⁶ O ² S, 454.22, m/z found, 455.2 [M+H]+.1H NMR (400 MHz, DMSO-afe): 511.91 (s, 1H), 8.55 (s, 1H), 7, 86 -7.74 (m, 1H), 7.51 - 7.42 (m, 1H), 6.73 (s, 1H), 4.76 -4.62 (m, 1H), 4.56 (d, J = 5.6 Hz, 2H), 3.14 - 3.03 (m, 1H), 2.60 (d, J = 5.6 Hz, 2H), 2.43-2.32 (m, 2H), 2.09-1.94 (m, 7H), 1.82-1.70 (m, 2H), 1.65 -1.55 (m, 1H), 1.51 -1.29 (m, 4H), 1.25-1.08 (m, 3H).

Reference Example 142 Synthesis and Characterization:

2-((fr,4r,)-4-(2-(((Dimethyl(oxo)-A6-sulfanylidene)amino)methyl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin- 1(6Hj-yl)cyclohexyl)acetonitrile

[0579]

[0580] A solution of 2-((7r,4rM-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile (Intermediate 8, 91 mg, 0.19 mmol), (S-methylsulfonimidoyl)methane (48 mg, 0.52 mmol) and NaHCO3 (25 mg, 0.29 mmol) in CH ³ CN (3 mL) heated at 130 °C for 20 hours The reaction was concentrated to dryness and the residue was dissolved in MeOH/THF/NaOH (1 M) (1 mL/1 mL/1 mL) and heated at 80 °C for 1 h The reaction was concentrated to dryness and partitioned between CH ² Cl ² (5 mL) and water (5 mL), the organic layer was collected and concentrated to dryness, the residue was purified by flash column chromatography to give the title compound (31 mg, 42% yield) MS (ESI): mass calcd for C ¹⁹ H ²⁴ N ⁶ OS, 384.17, m/z found, 385.2 [M+H]+ 1H NMR (400 MHz, CDCh): 5 11.76 - 11.30 (s, 1H), 8.95 - 8.49 (s, 1H), 7.52 - 7.31 (m, 1H), 6, 85 - 6.49 (d, J = 3.4 Hz, 1H), 4.93 - 4.41 (m, 3H), 3.16 -2.94 (s, 6H), 2.62 - 2, 30 (m, 4H), 2.20 - 2.00 (m, 5H), 1.53-1.36 (m, 2H).

Re fere n ce e xample 143 S in te sis an d c a c ter iz a tio n:

2-((ir,4rt-4-(2-(4-(Pentafluoro-A6-sulfanyl)phenyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile

[0581]

[0582] Step A: 2-(( 1r,4r)-4-(2-(4-(Pentafluoro-A6-sulfanyl)phenyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile. 2-(( 7r,4r^-4-((5-Nitro-1 -(phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 120 mg, 0.273 mmol) was dissolved in DMSO (2.3 mL) and MeOH (0.5 mL) in a microwave vial 4-(pentafluorothio)benzaldehyde (139 mg, 0.599 mmol) was added followed by Na2S2O4 (140 mg , 0.683 mmol) and the vial was stoppered and heated at 100 °C over the weekend. After cooling to room temperature, the mixture was diluted with water (5 mL) and stirred for 5 minutes. The tan precipitate that was formed was collected by filtration, washed with water (50 mL) and allowed to dry completely.The solid was collected in a round bottom flask by dissolving in EtOAc.The organic phase was then concentrated to dryness to give the compound of titer as tan solid, used without further purification MS (ESI): mass calcd for C ²⁸ H ²⁴ F ⁵ N ⁵ O ² S ² , 621.13, m/z found, 622.2 [ M+H]+.

[0583] Step B: 2-(( ír,4rt-4-(2-(4-(Pentafluoro-A6-sulfanyl)phenyl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridine- 1(6H)-yl)cyclohexyl)acetonitrile The title compound (94.6 mg, 72% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2-((1r,4r) -4-(2-(4-(Pentafluoro-A6-sulfanyl)phenyl)-6-(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile (169 mg, 0.272 mmol) in place of 2- ( 1- (( 1r,4r)-4- (Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a] pyrrolo[2,3-b]pyr'idin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide The crude material was triturated with heptane and DCM and then collected by vacuum filtration to give the title compound MS (ESI): mass calcd for C ²² H ²⁰ F ⁵ N ⁵ S, 481.14, m/z found, 482.1 [M+H]+ 1H NMR (400 MHz, DMSO- afe): 512.05 (s, 1H), 8.68 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 3.0 Hz, 1H), 6.81 (d, J = 3.3 Hz, 1H), 4.50 -4.2 8 (m, 1H), 2.55 (d, J = 6.3 Hz, 2H), 2.48 - 2.38 (m, 2H), 2.12 - 2.01 (m, 3H), 2 0.01-1.93 (m, 2H), 1.39-1.24 (m, 2H).

Reference Example 144 Synthesis and Characterization:

N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-fo]pyridin-2-yl)methyl)- 1 H-pyrazole-4-carboxamide

[0584]

[0585] Step A: N- (( 1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2 -yl)methyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide. A solution of 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile solution (Intermediate 5, 170 mg, 0.493 mmol), (carbonic isobutyl) 1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazole-4-carboxylic anhydride, prepared in Example 137, Step C, (199 mg, 0.493 mmol) 4-methylmorpholine (150 mg, 1.48 mmol) and dry THF (5 mL) and stirred for 18 h at 25 °C. The reaction was concentrated to dryness and the residue dissolved in CH ² Cl (20 mL). The organic phase was washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC using an Agela DuraShell 150 mm x 25 mm, 5 gm column (eluent: 32% to 62% (v/v) CH ³ CN and H ² O with 10 mM NH ⁴ HCO ³ ) to provide the title compound (60 mg, 22% yield) as a white solid. MS (ESI): mass calc. for C27H36NbO2S¡, 532.27; m/z found, 533.1 [M+H]+. 1H NMR (400MHz, CDCh): 10.34 (s, 1H), 8.73 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.48-7 .31 (m, 2H), 6.76 -6.69 (m, 1H), 5.44 (s, 2H), 4.98 (d, J = 5.2 Hz, 2H), 4.77 - 4.63 (m, 1H), 3.63 -3.52 (m, 2H), 2.42 (d, J = 6.8 Hz, 2H), 2.25 - 2.13 (m, 2H) , 2.11-1.97 (m, 3H), 1.90-1.66 (m, 2H), 1.56-1.40 (m, 2H), 0.94 -0.86 (m, 2H), -0.03 (s, 9H).

[0586] Step B: N-((1 -((7r,4rM-(C¡anomethyl)cyclohex¡l)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)methyl)-1 H-pyrazole-4-carboxamide A solution of N-((1-((7r,4r^4-(cyanomethyl)c¡clohex¡l)-1,6 -d¡h¡dro¡m¡dazo[4,5-a(]p¡rrolo[2,3-b]p¡r¡d¡n-2-yl)methyl)-1 -((2-( trimethyls¡l¡l)ethoxy¡)methyl)-1H-pyrazole-4-carboxamide (50 mg, 0.094 mmol) and TFA (2 mL) were stirred for 0.5 h at 10 °C. The reaction was concentrated to dryness, the residue dissolved in water (5 mL) and the aqueous phase adjusted to pH = 7-8 with saturated aqueous NaHC03 The precipitate was filtered, washed with water (2 mL X 3) and lyophilized to provide the title compound (38 mg, 99% yield) as an off-white solid MS (ESI): mass calcd for C ²¹ H ²² N ⁸ O, 402.19, m/z found, 403, 2 [M+H]+ .1H NMR (400 MHz, DMSO-ds): 13.15 (s, 1H), 11.88 (s, 1H), 8.77 (s, 1H), 8.55 (s, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.46 (s, 1H), 6.71 (s, 1H), 4.84 (s, 2H) , 4.69 -4.49 (m, 1H), 2.63 - 2.55 (m, 2H), 2.40 -2.21 (m, 2H), 2.09-1.71 (m, 4H), 1.45-1.09 (m, 3H).

Reference Example 145: Synthesis and Characterization:

1-((7r,4r^4-(c¡anomet¡l)c¡clohex¡l)-N-(2-methox¡et¡l)-1 ^-dihydroimidazo^^-adpyrrolo^^-fojpyridin^- carboxamide

[0587]

[0588] The title compound (40 mg, 52% yield) was prepared using analogous conditions to those described in Example 50, Step A using 2-methoxyethanamine in place of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²⁰ H ²⁴ N ⁶ O ² , 380.20; m/z found, 381.2 [M+H]+. 1H NMR (500 MHz, CDCl): 10.83 (s, 1H), 8.84 (s, 1H), 8.11 (t, J =5.8 Hz, 1H), 7.55-7, 40 (m, 1H), 6.91 -6.73 (m, 1H), 6.32 - 5.75 (m, 1H), 3.79 - 3.56 (m, 4H), 3.44 ( s, 3H), 2.78 - 2.55 (m, 2H), 2.40 (d, J = 6.6 Hz, 2H), 2.28 - 2.00 (m, 5H), 1.62 -1.38 (m, 2H).

Reference Example 146 Synthesis and Characterization:

(1 -((Ir^rM^CyanometiOcyclohexylH ^-dihydroim idazo^^-adpyrrolo^^-bjpyridin^-yl(cyclohexylmethyl)carbamate)methyl

[0589]

[0590] Step A: (1 -((fr^rM-fcyanometiOcyclohexyO^-^enylsulfonylH ^ -d ih id ro im idazo^^-d^ irro lo^^-^p irid in^-iOmeti^cyclohexylmetiOcarbamate. A solution of 2-((fr,4r,)-4-(2-(h¡droxmethyl)-6-(fen¡lsulfon¡l)¡m¡dazo[4,5-a(|p¡rrolo [2,3-b]p¡r¡d¡n-1(6H)-¡lo)c¡clohex¡l)aceton¡trilo (intermediate 7, 34 mg, 0.076 mmol), (isocyanatomethylOcyclohexane (28 mg , 0.20 mmol), triethylamine (42 mL, 0.30 mmol), and DMF (1 mL) was heated to 80 °C for ~15 min, then stirred at room temperature over the weekend. The reaction was concentrated. to dryness and the residue was purified by flash column chromatography (12 g silica gel column, 20-100% EtOAc in heptanes) to provide the title compound (42 mg, 94% yield) as a clear oil. MS (ESI): mass calcd for C ³¹ H ³⁶ N ⁶ O ⁴ S, 588.25, m/z found, 589.3 [M+H]+.

[0591] Step B: (1 -((fr^í^M^CianometiOcyclohexylH ^-d ih idro im idazo^^-c/lp irro lo^^-^p irid in^-yl) (methyl cyclohexylmethylOcarbamate. A mixture of (1-((7r,4r,M-(c¡anomethyl)c¡clohex¡l)-6-(phen¡lsulfon¡l)-1,6-dihydroimidazo^^-adpyrrolo^^-blpyridin ^-iOmetiKcyclohexylmethylOcarbamate (42 mg, 0.071 mmol), 1 M NaOH (aq) (0.20 mL, 0.20 mmol), THF (1 mL), and MeOH (1 mL) were stirred at RT for 18 h and concentrated in vacuo The residue was purified by flash column chromatography (2-10% MeOH in CH ² Cl ² ) to give the title compound as an off-white solid (22 mg, 69% yield) MS (ESI): mass calc for C ²⁵ H ³² N ⁶ O ² , 448.26, m/z found, 449.3 [M+H]+.

1H NMR (400 MHz, CDCla) 5 = 11.25 (br s, 1H), 8.85-8.77 (m, 1H), 7.47-7.43 (m, 1H), 6.75 - 6.68 (m, 1H), 5.48 (s, 2H), 5.23 (br s, 1H), 4.56 (br s, 1H), 3.08 (t, J =6.3 Hz, 2H), 2.53 (br s, 2H), 2.42 ( d, J =7.1 Hz, 2H), 2.17 (d, J =12.1 Hz, 2H), 2.12-1.91 (m, 4H), 1.77-1.60 (m , 5H), 1.56-1.36 (m, 2H), 1.30-1.08 (m, 2H), 1.00-0.82 (m, 2H).

Reference Example 147 Synthesis and Characterization:

2-((1r,4r)-4-(2-(1-acetylazetidin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 ( ⁶ H)-yl)cyclohexyl )acetonitrile

[0592]

[0593] To a solution of 2-((1r,4r)-4-(2-(azetidin-3-yl)-6-((4-bromophenyl)sulfonyl)imidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (50 mg, 0.090 mmol), as prepared in Example 128, Step B, and DIPEA (3equiv.) in CH ² Cl ² (5 mL ) was added acetyl chloride ( ^8.5 mg, 0.11 mmol) in THF (0.5 mL) and stirred at room temperature for 1 hour. Water (20 ml) was added and the organic layer was collected and concentrated to dryness. The residue was dissolved in THF/MeOH/NaOH (1 M) (1 mL/1 mL/1 mL) and heated at 80 °C for 1 h. The reaction was concentrated to dryness and the residue was purified by flash column chromatography to provide the title compound (15 mg, 44% yield). MS (ESI): mass calc. for C ²¹ H ²⁴ N ⁶ O, 376.20; m/z found, 377.0 [M+H]+. 1H NMR (500 MHz, CDCh): 10.64 - 10.47 (m, 1H), 8.81 (s, 1H), 7.43 (d, J =3.5 Hz, 1H), 6, 69 (d, J = 3.5 Hz, 1H)), 5.02 (dd, J = 8.2, 6.0 Hz, 1H), 4.64 - ^{4 , 4 4} (m, 2H), 4 .32 - 4.07 (m, 2H), 3.54 - 3.41 (m, 1H), 2.64 - 2.39 (m, 4H), 2.27 - 2.14 (m, 2H) , 2.12-1.88 (m, ^6H ), 1.55 1.41 (m, 1H), 1.32-1.17 (m, 1H).

Reference Example 148 Synthesis and Characterization:

N- (( 1- (( 1r,4r)-4- ( C'ianomethyl)c'¡clohexyl)-1 ,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)methyl)benzamide

[0594]

[0595] Benzoyl chloride (55.6 mg, 0.396 mmol) was added dropwise to a solution of 2- (( 1r,4r)-4- ( 2- (aminomethyl)imidazo[4,5-d) hydrochloride ]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 5, 150 mg, 0.396 mmol), triethylamine (0.276 mL, 1.98 mmol), and CH ² CL (5 mL) and the reaction mixture was stirred for 1 hour at 10 °C. The reaction was diluted with CH ² Cl ^{2 (10} mL), washed with water ⁽¹⁰ mL), dried over anhydrous Na ² SO ⁴ , filtered, and concentrated to dryness. The residue was purified by preparative TLC (eluent: CH ² Cl ² : methanol = 10:1) twice to give the title compound (20 mg, 12% yield) as a white solid. MS (ESI): mass calc. for C ²⁴ H ²⁴ N ⁶ O, 412.20; m/z found, 413.2 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 511.88 (s, 1H), 9.19 (s, 1H), 8.55 (s, 1H), 7.92 (d, J = 7.6 Hz , 2H), 7.58 - 7.51 (m, 1H), 7.51 - 7.37 (m, 3H), 6.71 (s, 1H), 4.91 (d, J = 4.8 Hz, 2H), 4.72 -4.58 (m, 1H), 2.57 (d, J = 6.0 Hz), 2H), 2.41 - 2.27 (m, 2H), 2, 07-1.80 (m, 5H), 1.43-1.28 (m, 2H).

Reference Example 149: Synthesis and Characterization:

2-((1r,4r)-4-(2-(2-((R)-2-(Hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-a]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0596]

[0597] To a solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)acetate (intermediate 4, 300 mg crude, 0.835 mmol), L-prolinol (126 mg, 0.918 mmol) and DIPEA (0.291 mL, 1.67 mmol) in dry DMF (5 mL), PyBrOP ( 428 mg, 0.918 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (10ml) and extracted with ethyl acetate (20ml X 3). Both the organic and aqueous phases were concentrated to provide a residue which was initially purified by preparative HPLC using an Xtimate C ¹⁸ 150 X 25 mm X 5 pm column (eluent: 16% to 36% (v/v) CH ³ CN and H ² O with 10 mM NH ⁴ HCO ³ ) and then further purified by preparative TLC (dichloromethane:methanol = 15:1) to give the title compound (19 mg, 5% yield) as a white solid. MS (ESI): mass calc. for C ²³ H ²⁸ N ⁶ O ² , 420.23; m/z found, 421.2 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 511.83 (br s, 1H), 8.49 (s, 1H), 7.48-7.44 (m, 1H), 6.71 (br s, 1H), 5.15 (t, J = 4.0 Hz, 0.3H), 4.79 (t, J = 4.0 Hz, 0.7H), 4.45-4.20 (m, 2H ), 4.19 -4.11 (m, 1H), 3.99 - 3.92 (m, 1H), 3.65 - 3.57 (m, 1H), 3.56 - 3.43 (m , 2H), 3.32 - 3.25 (m, 2H), 2.60 - 2.55 (m, 2H), 2.39 - 2.25 (m, 2H), 2.06-1.81 (m, 8H)), 1.43-1.27 (m, 2H).

Reference Example 150 Synthesis and Characterization:

( Z*)-N'- (( 1- (( 1r,4r)-4- ( Cyanomethyl)cyclohexyl)-1 ,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methoxy)isobutyrimidamide; the structure being the (Z) or (E) isomer, and the (Z) notation and its corresponding structure below are chosen arbitrarily

[0598]

[0599] Step A: (Z*)-N'-((1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d] pyrrolo[2,3-b]pyridin-2-yl)methoxy)isobutyrimidamide. A solution of 2-((1r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-a(]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile (intermediate 8, 250 mg, 0.534 mmol), N'-hydroxy-2-methylpropanimidamide (164 mg, 1.60 mmol), K ² CO ³ (369 mg, 2.67 mmol) and DMF ( 4 mL) was stirred for 18 h at 50 C. The reaction mixture was concentrated to dryness to provide the title compound (780 mg, 95.8% yield), which was used in the next step without further purification.MS (ESI): mass calcd for C ²⁷ H ³¹ N ⁷ O ³ S, 533.22, m/z found, 534.0 [M+H]+.

[0600] Step B: (Z*)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)methoxy)isobutyrimidamide. The title compound (50 mg, 24% yield) was prepared as a white solid using analogous conditions to those described in Example 1, Step B using (Z*)-N'-((1-((1r,4r )-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methoxy)isobutyrimidamide (780 mg, 0. 51 mmol) instead of 2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. The title compound was purified by preparative HPLC using a Phenomenex Gemini 150 mm x 25 mm column, 5 pm (eluent: 20% to 50% (v/v) of CH ³ CN and H ² O with 0.05% of ^NH3 ). MS (ESI): mass calc. for C ²¹ H ²⁷ N ⁷ O, 393.23; m/z found, 394.2 [M+H]+. 1H NMR (400 MHz, DMSO-da): 511.87 (s, 1H), 8.53 (s, 1H), 7.50-7.41 (m, 1H), 6.71 (d, J = 1.6 Hz, 1H), 5.64 (s, 2H), 5.15 (s, 2H), 4.80 -4.64 (m, 1H), 2.56 (d, J = 6.4 Hz, 2H), 2.40 -2.27 (m, 2H), 2.26 - 2.17 (m, 1H), 2.09-1.88 (m, 5H), 1.47-1, 31 (m, 2H), 1.01 (d, J =6.8Hz, 6H).

Reference Example 151 Synthesis and Characterization:

(Z * )-N '-( (1 -( (1 r ,4 r) -4 -(C ia nome til)c ic lo hex il) -1 ,6 -d ih id ro im idazo [4 , 5 -a ( ]p ir ro lo [2 ,3 -> ]p ir id in -2 -il)me to xi) c ic lo pro panoca rb oxi im id am id a ; being the est ru c tu ra el isómero (Z ) or (E ), and the nota tio n (Z ) and its corre spond ie n s tru c tu ra te cont in uat io n see lig ena arbitra r iamen tea

[0601]

[0602] Step A: (Z*)-N'-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6 dihydroimidazo[4,5-d] pyrrolo[2,3-b]pyridin-2-yl)methoxy)cyclopropanecarboximidamide. A solution of 2-((1r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile (intermediate 8, 250 mg, 0.534 mmol), N'- hydroxycyclopropanecarboximidamide (160 mg, 1.60 mmol), K ² CO ³ (369 mg, 2.67 mmol) and DMF (4 mL) were stirred for 18 h at 50 °C. The reaction was concentrated to dryness to provide the title compound (780 mg, 96% yield), which was used in the next step without further purification. MS (ESI): mass calc. for C ²⁷ H ²⁹ N ⁷ O ³ S, 531.21; m/z found, 532.1 [M+H]+.

[0603] Step B: (Z*)-N'-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-c/]pyrrolo[2, 3-¿>]pyridin-2-yl)methoxy)cyclopropanecarboximidamide. The title compound (35 mg, 17% yield) was prepared as a white solid using conditions analogous to those described in Example 1, Step B using ( Z)-N'- (( 1- (( 1r,4r) -4- (cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methoxy)cyclopropanecarboximidamide (780 mg, 0. 51 mmol) in place of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3 -b]pyridin-2-yl)-N-('2-hydroxy-2-methylpropyl)acetamide. The title compound was purified by preparative HPLC using a Phenomenex Gemini 150 mm x 25 mm column, 5 pm (eluent: 20% to 50% (v/v) of CH ³ CN and H ² O with 0.05% of ^NH3 ). MS (ESI): mass calc. for C ²¹ H ²⁵ N ⁷ O, 391.21; m/z found, 392.2 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 511.88 (s, 1H), 8.54 (s, 1H), 7.47 (t, J = 3.2 Hz, 1H), 6.73 (s , 1H), 5.57 (s, 2H), 5.15 (s, 2H), 4.80 - 4.67 (m, 1H), 2.58 (d, J = 6.4 Hz, 2H) , 2.42 - 2.27 (m, 2H), 2.09-1.90 (m, 5H), 1.50 1.35 (m, 2H), 1.35-1.26 (m, 1H ), 0.69-0.55 (m, 4H).

Reference Example 152 Synthesis and Characterization:

(3R,5R,7R,E*)-N'-((1-((1 r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2, 3-b]pyridin-2-yl)methoxy)adamantane-1-carboximidamide; the structure being the (Z) or (E) isomer, and the (Z) notation and its corresponding structure below are chosen arbitrarily

[0604]

[0605] Step A: ( 3R,5R,7R,E*)-N'- (( 1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo [4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methoxy)adamantane-1-carboximidamide. A solution of 2-((1r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile (Intermediate 8, 76 mg, 0.16 mmol), (3R,5R,7R,Z)-N'-hydroxyadamantane-1-carboximidamide (80 mg, 0.41 mmol), K ² CO ³ ( 82 mg, 0.59 mmol) and ^{dM f} (2 mL) was stirred at room temperature for 45 h. After filtering off the solid, the filtrate was concentrated to dryness to provide the title compound (100 mg, 98% yield). MS (ESI): mass calc. for C ³⁴ H ³⁹ N ⁷ O ³ S, 625.28; m/z found, 626.4 [M+H]+.

[0606] Step B: ( 3R,5R,7R,E*)-N'- (( 1 -((1 r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)methoxy)adamantane-1-carboximidamide. A solution of ( 3R,5R,7R,E*)-N'- (( 1- (( 1r,4r)-4- ( cyanomethyl)cyclohexyl)-6- (phenylsulfonyl)-1,6 dihydroimidazo[4,5 -d]pyrrolo[2,3-b]pyridin-2-yl)methoxy)adamantane-1-carboximidamide (100 mg, 0.16 mmol) in THF (0.7 mL) and MeOH (0.7 mL) were added. treated with 3N NaOH (0.21 mL) mL, 0.64 mmol) for 18 h at room temperature. After concentration in vacuo, the residue was purified by RF-HPLC (10 - 90% CH ³ CN in H ² O, 0.1% of TFA). The collected fractions were concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHC03 solution. The aqueous layer was extracted with EtOAc (x 4). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to provide the title compound (19 mg, 24%). MS (ESI): mass calc. for C ²⁸ H ³⁵ N ⁷ O, 485.29; m/z found, 486.3 [M+H]+. 1H NMR (400 MHz, CDCh) 5 = 11.04 (br s, 1H), 8.80 (s, 1H), 7.44 (br s, 1H), 6.75 -6.69 (m, 1H ), 5.82 (br s, 1H), 5.65 (open, 1H), 4.83 -4.67 (m, 1H), 4.49 (open, 2H), 2.66 - 2.49 (m, 2H), 2.43 (d, J =6.1 Hz, 2H), 2.22-2.10 (m, 2H), 2.10-1.96 (m, 3H), 1, 88 (d, J =3.0 Hz, 4H), 1.82 (d, J =2.5 Hz, 4H), 1.77-1.63 (m, 7H), 1.58-1.34 (m, 2H).

Reference Example 153 Synthesis and Characterization:

(Z*)-N'-((1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a(|pyrrolo[2,3-b]pyridin- 2-yl)methoxy)-2-(piperidin-1-yl)acetimidamide; the structure being the (Z) or (E) isomer, and the (Z) notation and its corresponding structure below are chosen arbitrarily

[0607]

[0608] Step A: N'-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2, 3-b]pyridin-2-yl)methoxy)-2-(piperidin-1-yl)acetimidamide. The title compound was prepared using analogous conditions to those described in Example 152, Step A using N-hydroxy-2-(piperidin-1-yl)acetimidamide in place of (3R,5R,7R)-N'-hydroxyadamantane- 1-carboximidamide to provide the title compound (113 mg, 100%). MS (ESI): mass calc. for C ³⁰ H ³⁶ N ⁸ O ³ S, 588.26; m/z found, 589.3 [M+H]+.

[0609] Step B: N'- (( 1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)methoxy)-2-(piperidin-1-yl)acetimidamide. The title compound was prepared using analogous conditions to those described in Example 152, Step B using N'-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methoxy)-2-(piperidin-1-yl)acetimidamide (113 mg, 0.190 mmol) in place of ( 3R, 5R,7R)-N'- (( 1- (( 1r,4r)-4- (cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6 dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridine-2-yl)methoxy)adamantane-1-carboximidamide to give the title compound (22 mg, 26%). The title compound was initially purified by flash column chromatography (12 g silica gel column, 2-20% MeOH in DCM). Subsequently, it was further purified by reverse phase HPLC (5-95% CH ³ CN in H ² O, 0.1% TFA). Pure fractions from the HPLC purification were concentrated and dissolved in 10% MeOH/DCM, passed through a 500 mg SILICYCLE SPE-R66030B-03P carbonate column to remove TFA and eluted with 10% MeOH. in DCM. MS (ESI): mass calc. for C ²⁴ H ³² N ⁸ O, 448.27; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, CDCh) 5 = 10.65 (br s, 1H), 8.81 (s, 1H), 7.45-7.42 (m, 1H), 6.73 (d, J= 2.5 Hz, 1H), 5.40 (br s, 1H), 5.32 (s, 2H), 4.79 -4.63 (m, 1H), 3.14 (br s, 2H), 2.73 - 2.47 (m, 5H), 2.44 (d, J =6.1 Hz, 2H), 2.28 - 2.11 (m, 3H), 2.11-1.89 ( m, 3H), 1.71-1.59 (m, 4H), 1.59-1.39 (m, 4H).

Reference Example 154 Synthesis and Characterization:

neopentyl ((1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate

[0610]

[0611] Neopentyl chloroformate (69.9 mg, 0.464 mmol) was added dropwise to a solution of 2- (( 1r,4r)-4- ( 2- (aminomethyl)imidazo[4,5-d]hydrochloride of pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 5, 160 mg, 0.422 mmol), triethylamine (0.294 mL, 2.11 mmol), and CH ² Cl ² (5 mL ) and stirred for 30 min at 10 °C. The reaction mixture was diluted with CH ² Cl ² (10 mL), washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC (eluent: CH ² Cl ² : methanol = 10:1) to give the title compound (50 mg, 28% yield) as a white solid. MS (ESI): mass calc. for C ²³ H ³⁰ N ⁶ O ² , 422.24; m/z found, 423.2 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 11.87 (s, 1H), 8.54 (s, 1H), 7.84 (s, 1H), 7.47 (t, J = 2.8 Hz, 1H), 6.71 (s, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.58 -4.47 (m, 1H), 3.71 (s, 2H ), 2.59 (d, J = 5.6 Hz, 2H), 2.43-2.25 (m, 2H), 2.08-1.84 (m, 5H), 1.47-1, 32 (m, 2H), 0.89 (s, 9H).

Reference Example 155 Synthesis and Characterization:

1-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)methyl)- 3-(cyclohexylmethyl)urea

[0612]

[0613] Step A: 1-((1 - (( 1r,4r)-4- (Cyanomethyl)c¡clohex¡l)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo [2,3-b]pyridin-2-yl)methyl)-3-(cyclohexylmethyl)urea. The title compound (185 mg) was prepared using conditions analogous to those described in Example 70, Step C using (isocyanatomethyl)cyclohexane (101 mg, 0.726 mmol) in place of isocyanatobenzene. The compound was purified by flash column chromatography (12 g silica gel column, 2-10% MeOH in DCM). MS (ESI): mass calc. for C ³¹ H ³⁷ N ⁷ O ³ S, 587.27; m/z found, 588.3 [M+H]+.

[0614] Step B: 1-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2 -yl)methyl)-3-(cyclohexylmethyl)urea. The title compound was prepared using the product from Step A (Example 155, Step A) using analogous conditions to those described in Example 1, Step B (67 mg, 48% yield). The compound was purified by flash column chromatography (12 g silica gel column, 2-10% MeOH in DCM). MS (ESI): mass calc. for C ²⁵ H ³³ N ⁷ O, 447.27; m/z found, 448.4 [M+H]+. 1H NMR (400 MHz, CDCh) 5 = 11.95 (br s, 1H), 8.71 (s, 1H), 7.44 (t, J = 2.8 Hz, 1H), 6.68 (br s, 2H), 5.44 (br s, 1H), 4.83 (br d, J = 5.6 Hz, 2H), 4.65 (br s, 1H), 3.01 (t, J = 6.1 Hz, 2H), 2.47 (br s, 2H), 2.32 (d, J =6.4 Hz, 2H), 2.14-1.87 (m, 5H), 1.67 -1.52 (m, 5H), 1.44-1.23 (m, 3H), 1.17-0.98 (m, 2H), 0.88-0.73 (m, 2H)).

Reference Example 156 Synthesis and Characterization:

( 3R,5R,7 R)-N- (( 1- (( 1r,4r)-4- ( Cyanomethyl)cyclohexyl)-1 ,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b] pyridin-2-yl)methyl)adamantane-1-carboximidamide

[0615]

[0616] Step A: (3R,5R,7R)-N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5 -d]pyrrolo[2,3-b]pyridin-2-yl)methyl)adamantane-1-carboximidamide. A solution of 2-((1r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile (Intermediate 8, 76 mg, 0.16 mmol), (3R,5R,7R)-adamantane-1-carboximidamide (88 mg, 0.41 mmol), K ² CO ³ (80 mg, 0, 58 mmol), and DMF (2 mL) was stirred at room temperature overnight. After filtering off the solid, the filtrate was concentrated to dryness to provide the title compound (98 mg, 99% yield) as an oil, which was carried on to the next step without further purification. MS (ESI): mass calc. for C ³⁴ H ³⁹ N ⁷ O ² S, 609.29; m/z found, 610.3 [M+H]+.

[0617] Step B: ( 3R,5R,7R)-N- (( 1- (( 1r,4r)-4- ( Cyanometh'¡l)c'¡clohexyl)-1 ,6-dihydroimidazo[4,5 -a(|pyrrolo[2,3-b]pyridin-2-yl)methyl)adamantane-1-carboximidamide A mixture of (3R,5R,7R)-N-('(1-((1r,4r) -4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)adamantane-1-carboximidamide (98 mg, 0.16 mmol), 3M NaOH(aq) (0.11 mL, 0.33 mmol), THF (1 mL), and MeOH (1 mL) was stirred at RT for 18 h and concentrated in vacuo. The residue was purified by reverse phase HPLC (10-90% CH ³ CN in H ² O, 0.1% TFA) to give a clear oil This material was partitioned between EtOAc and saturated NaHCO ³ (aq). aqueous layer was extracted with EtOAc (x 4) The combined organic phases were dried over Na2SO4, filtered and concentrated to give the title compound as an off-white solid (62 mg, 83%) MS (ESI): mass calc. for C ²⁸ H ³⁵ N ⁷ , 469.30, m/z found, 470.4 [M+H]+.

1H NMR (400 MHz, CDCh) 59.64 (br s, 1H), 8.75 (s, 1H), 7.45-7.41 (m, 1H), 6.76 (d, J =2, 0 Hz, 1H), 5.11 (br s, 2H), 4.74 (br s, 1H), 2.45 (br s, 2H), 2.39 (d, J =6.6 Hz, 2H ), 2.25-2.09 (m, 6H), 2.05-1.94 (m, 6H), 1.90-1.47 (m, 10H).

Example 157 Synthesis and characterization:

3-Cyano-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl )methyl)propanamide

[0618]

[0619] HATU (100 mg, 0.264 mmol) was added to a solution of 2-((1r,4r)-4-(2-(aminomethyl)imidazo[4,5-d]pyrrolo[2,3- b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (Intermediate 5, 100 mg, 0.264 mmol), 3-cyanopropanoic acid (26.1 mg, 0.264 mmol), DIeA (0.230 mL, 1.32 mmol) and CH ² Cl ² (5 mL) and stirred for 0.5 h at 10 °C. The reaction was diluted with CH ² Cl ² (10 mL), washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC (eluent: CH ² Ch : methanol = 10:1) to give the title compound (30 mg, 29% yield) as a white solid. MS (ESI): mass calc. for C ²¹ H ²³ N ⁷ O, 389.20; m/z found, 390.2 [M+H]+.

1H NMR (400 MHz, DMSO-afe): 511.90 (s, 1H), 8.76 (t, J = 5.6 Hz, 1H), 8.55 (s, 1H), 7.48 (t , J = 2.8 Hz, 1H), 6.73 (s, 1H), 4.72 (d, J = 5.6 Hz, 2H), 4.62 -4.47 (m, 1H), 2 .69 (t, J = 6.8 Hz, 2H), 2.57 (d, J = 6.0 Hz, 2H), 2.55 (t, J = 6.8 Hz, 2H), 2.43 - 2.24 (m, 2H), 2.11-1.87 (m, 5H), 1.47-1.30 (m, 2H).

Reference Example 158 Synthesis and Characterization:

ferrc-butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)methyl) carbamate

[0620]

[0621] Step A: tert-butyl ((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2, 3-b]pyridin-2-yl)methyl)carbamate. A solution of 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1 , 1.00 g, 2.28 mmol), ferrt -butyl(2-oxoethyl) carbamate (0.820 g, 5.20 mmol) and sodium hydrosulfite (1.17 g, 5.69 mmol) in DMSO (3 mL ), MeOH (10 mL) and distilled water (5 mL) was heated in a pressure tube at 100 °C for 15 h. The reaction was concentrated to dryness and the residue partitioned between CH ² Cl ² and water. The organic layers were combined, washed with water, and the aqueous layer was re-extracted with CH ² Cl ² . The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (36 g silica gel column, 30-100% EtOAc in heptanes) to provide the title compound (748 mg, 60% yield) as a white solid, MS ( ESI): calculated mass. for C ²⁸ H ³² N ⁶ O ⁴ S, 548.2; m/z found, 549.3 [M+H]+.

[0622] Step B: tert-butyl ((1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate. The title compound (64 mg, 86%) was prepared as a white solid using analogous conditions to those described in Example 156, Step B using ferrt-butyl ((1-((1r,4r)-4-(cyanomethyl) cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate (100 mg, 0.18 mmol) instead from (3R,5R,7R)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo [2,3-b]pyridin-2-yl)methyl)adamantane-1-carboximidamide The title compound was initially purified by reverse phase HPLC (10 - 90% CH ³ CN in H ² O, 0.1 The pure fractions were dissolved in 10% MeOH in DCM, passed through a 500 mg SILICYCLE SPE-R66030B-03P carbonate column to remove TFA and eluted with 10% MeOH in DCM. .MS (ESI): mass calcd for C ²² H ²⁸ N ⁶ O ² , 408.23, m/z found, 409.2 [M+H]+ .1H r Mn (400 MHz, CDCb) 5 = 11 .41 - 11.26 (m, 1H), 8.77 (s, 1H), 7.48 (t, J = 3.0 Hz, 1H), 6.76 -6.70 (m, 1H), 6.08 (br s, 1H), 4.75 (br d, J =6.1 Hz, 3H), 2.54 (br s, 2H), 2.42 (d, J =6.6 Hz, 2H), 2.24-2.09 (m, 3H), 2.09-1.95 (m, 3H), 1.87 (br s, 1H), 1.49 (m, 9H).

Reference Example 159 Synthesis and Characterization:

2-((1r,4r)-4-(2-(Azetidin-3-yl)imidazo[4,5-a(]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0623]

[0624] A solution of 2-((1r,4r)-4-((1-((4-bromophenyl)sulfonyl)-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl) amino)cyclohexyl)acetonitrile (519 mg, 1.00 mmol), prepared in Example 128, Step A, tert-butyl 3-formylazetidine-1-carboxylate, (371 mg, 2.00 mmol), sodium dithionite ( 523 mg, 3.00 mmol), DMSO (2.5 mL) and water (0.15 mL) were heated at 100 °C for 16 hours. Water (20ml) was added. The precipitate that formed was collected by filtration and purified by flash column chromatography. To this material was added CH ² Cl ² (5 mL) and TFA (1 mL) and stirred for 0.5 h. The reaction was concentrated to dryness. To the residue, CH ² Cl ² (10 mL) and saturated NaHCO ³ (10 mL) were added, the organic layer was collected and concentrated to dryness. The residue was dissolved in NaOH (1 M)/THF/MeOH (1 mL/1 mL/1 mL) and heated at 80 °C for 1 h. The reaction was concentrated to dryness and the residue was purified by flash column chromatography to provide the title compound (5.00 mg, 1% yield). MS (ESI): mass calc. for C ¹⁹ H ²² N ⁶ , 334.19; m/z found, 335.2 [M+H]+. 1H NMR (500 MHz, CDCla): 58.97 (s, 1H), 8.84-8.71 (m, 1H), 7.40-7.31 (m, 1H), 6.68 (d, J = 3.6 Hz, 1H), 4.38 - 4.20 (m, 3H), 4.04 - 3.87 (m, 3H), 2.68 - 2.32 (m, 4H), 2 .27-1.85 (m, 5H), 1.50-1.35 (m, 2H).

Example 160 Synthesis and characterization:

3-(3-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)azetidine -1 -yl)-3-oxopropanenitrile

[0625]

[0626] A solution of 2-((1r,4r)-4-(2-(Azetidin-3-yl)imidazo[4,5-a(]pyrrolo[2,3-b]pyridin-1(6H) -yl)cyclohexyl)acetonitrile (30.0 mg, 0.0900 mmol), prepared in Example 159, and 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (32.7 mg, 0.179 mmol) in CH ² Cl ² (2 mL) was stirred at room temperature for 4 h Water (1 mL) was added and the organic phase was collected and concentrated to dryness The residue was purified by flash column chromatography to give the title compound (9 mg, 25% yield) M ^s (ESI): mass calcd for C ²² H ²³ N ⁷ O, 401.2, m/z found, 402.2 [M+H]+ 1H NMR (400 MHz , CDCla): 59.45 (s, 1H), 8.79 (s, 1H), 7.49 - 7.34 (m, 1H), 6.81 -6.54 (m, 1H), 5, 21 - 5.02 (m, 1H), 4.77 (t, J = 8.5 Hz, 1H), 4.57 (t, J = 9.2 Hz, 1H), 4.47 - 4.29 (m, 1H), 4.32 - 4.12 (m, 1H), 3.78 - 3 .52 (m, 1H), 3.37 (d, J = 3.8 Hz, 2H), 2.54 -2.40 (m, 4H), 2.33-1.91 (m, 5H), 1.53-1.37 (m, 2H).

Reference Example 161 Synthesis and Characterization:

(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)methyl (2-methoxyethyl) carbamate

[0627]

[0628] Step A: (1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b/ pyridin-2-yl)methyl(2-methoxyethyl)carbamate. A solution of 2-(( 7r,4rJ-4-(2-(hydroxymethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile (Intermediate 7, 100 mg, 0.222 mmol) and 1-isocyanato-2-methoxyethane (45 mg, 0.45 mmol) was heated at 60 °C for 16 h LCMS showed starting material remaining, therefore which was continued to heat for 24 h, after which more 1-isocyanato-2-methoxyethane (45 mg, 0.45 mmol) was added and the reaction heated at 60 °C for 18 h, then warmed to 80 °C. C for 68 h The reaction was concentrated to dryness and the residue was purified by flash column chromatography (12 g silica gel column, 0-100% EtOAc in heptanes, then 10% MeOH in DCM) to give the title compound as an impure mixture (2:1 product and starting material, 159 mg) as an off-white solid which was used as is in the subsequent reaction MS (ESI): mass calcd for C ²⁷ H ³⁰ N ⁶ O ⁵ S, 550.2, m/z found, 551.2 [M+H]+.

[0629] Step B: (1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl) methyl (2-methoxyethyl)carbamate. The title compound (30 mg, 25%) was prepared using analogous conditions to those described in Example 156, Step B using (1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl) -1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl)methyl(2-methoxyethyl)carbamate (159 mg, 0.290 mmol) in place of (3R,5R, 7R)-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b] pyridin-2-yl)methyl)adamantane-1-carboximidamide The compound was purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 x 30 mm column (eluent: 5-95% CH ³ CN in H ² O, 0.1% TFA) Pure fractions were concentrated and dissolved in 10% MeOH/DCM, passed through a 500 mg SILICYCLE SPE-R66030B-03P carbonate column to remove TFA and eluted with MeOH 10% in DCM MS (ESI): mass calcd for C ²¹ H ²⁶ N ⁶ O ³ , 410.2, m/z found, 411.3 [M+H]+ 1H NMR (400 MHz, CDCh ) 5 = 11.51 (br s, 1H), 8.82 (s, 1H), 7.46 (t, J = 2.8 Hz, 1H), 6.74 -6.64 (m, 1H), 5.70 (br s, 1H), 5.48 (s, 2H), 4.52 (br s, 1H), 3.53 - 3.47 (m, 2H), 3.47 - 3.40 (m, 1H), 3.38 - 3.29 (m, 3H), 2.52 (br s, 2H), 2 .41 (d, J = 6.6 Hz, 2H), 2.23-1.91 (m, 6H), 1.56-1.34 (m, 2H).

Reference Example 162 Synthesis and Characterization:

2-((1r,4r)-4-(2-((((R)-Methyl(oxo)(phenyl)-A6-sulfanilidene)amino)methyl)imidazo[4,5-a]pyrrolo[2,3 -b]pyridin-1 ( 6H)- yl)cyclohexyl)acetonitrile

[0630]

[0631] ^{A solution of 2-((1r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[4,5 -a ]p ir ro lo [2 ,3 -b ]p ir id in -1 (6 H ) -} il) c ic lo hex il)ace to n it ri lo ( In te rm ed io 8 , 91 mg , 0.19 mmol) , (R )-(S -methyl sulfonimid or yl)benzene (36 mg , 0.23 mmol) and N to HCO 3 (24.5 mg , 0.292 mmol) were mixed Bottle in CH 3C N (3 ml) and dry slowly at 130 °C for 20 hours. The reaction was concentrated to dryness and the residue was dissolved in MeOH/THF/NaOH (1 M) (1 mL/1 mL/1 mL) and heated at 80 °C for 1 h. The reaction was concentrated to dryness and the residue partitioned between CH ² Cl ² and water (5ml/5ml). The organic layer was collected, concentrated to dryness and the residue was purified by flash column chromatography to give the title compound (10 mg, 12% yield). Ms (ESI): mass calc. for C ²⁴ H ²⁶ N ⁶ OS, 446.2; m/z found, 447.2 [M+H]+. 1H NMR (400 MHz, CDCla): 510.53 - 10.14 (m, 1H), 8.74 - 8.57 (m, 1H), 7.99 - 7.82 (m, 2H), 7, 69 - 7.45 (m, 3H), 7.41 - 7.26 (m, 1H), 6.79 -6.58 (m, 1H), 4.92 - 4.62 (m, 1H), 4.58 -4.36 (m, 1H), 4.36 -4.19 (m, 1H), 3.21 - 3.00 (m, 3H)), 2.64 - 2.28 (m, 4H), 2.22-1.95 (m, 5H), 1.57-1.34 (m, 2H).

Reference Example 163 Synthesis and Characterization:

2-((7r,4r)-4-(2-((((S)-methyl(oxo)(phenyl)-A6-sulfanylidene)amino)methyl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0632]

[0633] The title compound (42 mg, 48% yield) was prepared using conditions analogous to Example 163 using 2-((7r,4r)-4-(2-(chloromethyl)-6-(phenylsulfonyl)imidazo[ 4,5-c/]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (Intermediate 8, 91 mg, 0.19 mmol) and (S)-(S-methylsulfonimidoyl)benzene (36 mg, 0.23 mmol) in place of ( R )- ( S -methylsulfonimidoyl)benzene. MS (ESI): mass calc. for C ²⁴ H ²⁶ N ⁶ OS, 446.2; m/z found, 447.2 [M+H]+. 1H NMR (500 MHz, CDCla) 511.41 - 11.18 (s, 1H), 8.93 - 8.57 (s, 1H), 8.10 - 7.82 (m, 2H), 7.74 - 7.46 (m, 3H), 7.42 - 7.29 (m, 1H), 6.91 -6.55 (d, J = 3.2 Hz, 1H), 5.04 -4.68 (m, 1H), 4.62 -4.38 (d, J = 14.3 Hz, 1H), 4.38 -4.19 (m, 1H)), 3.32 - 2.92 (m, 3H), 2.58-2.32 (m, 4H), 2.20-1.98 (m, 5H), 1.58-1.35 (m, 2H).

Reference Example 164 Synthesis and Characterization:

2-((7r,4r)-4-(2-(1-acetylpiperidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-//)cyclohexyl )acetonitrile

[0634]

[0635] Step A: tert-butyl 4-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-2-yl)piperidine-1-carboxylate. To a solution of 2-((1r,4r)-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Al intermediate 2, 250 mg, 0.569 mmol) in DMSO (5 mL) and MeOH (1 mL) in a microwave vial was added 1-Boc-4-piperidinecarboxaldehyde (146 mg, 0.683 mmol), followed by sodium hydrosulfite ( 291mg, 1.42mmol). The vial was stoppered and heated at 100 °C overnight. After cooling to room temperature, the mixture was diluted with water (5 ml) and stirred for 5 minutes. The white precipitate that formed was collected by filtration, washed with water (50 ml) and allowed to dry completely. The solid was collected in a round bottom flask by dissolving in EtOAc. The organic phase was concentrated to dryness to give the title compound as a white solid, which was used without further purification. MS (ESI): mass calc. for C ³² H ³⁸ N ⁶ O ⁴ S, 602.3; m/z found, 603.3 [M+H]+.

[0636] Step B: 2-((7r,4r)-4-(6-(phenylsulfonyl)-2-(piperidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b) hydrochloride ]pyridine-1(6H)-yl)cyclohexyl)acetonitrile. To a solution of ferric-butyl 4-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6dihydroimidazo[4,5-a]pyrrolo[2,3-¿>]pyridin-2-yl )piperidine-1-carboxylate (336 mg, 0.557 mmol) in CH ² CI ² (3.9 mL) at room temperature was added 4 M HCl in dioxane (3.9 mL) and stirred at room temperature for 10 min. The reaction was concentrated to dryness and then dried in vacuo for 20 minutes to provide the title compound as the HCl salt as an off-white powder. MS (ESI): mass calc. for C ²⁷ H ³⁰ N ⁶ O ² S, 502.2; m/z found, 503.3 [M+H|+.

[0637] Step C: 2-((1r,4r)-4-(2-(1-acetylpiperidin-4-yl)-6-(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3-b ]pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. To a solution of 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-(piperidin-4-yl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1 To (6H)-yl)cyclohexyl)acetonitrile hydrochloride (100 mg, 0.185 mmol) in CH ² Cl ² (2.7 mL) was added triethylamine (0.258 mL, 1.86 mmol) and cooled to 0 °C. . Next, acetyl chloride (0.0158 mL, 0.223 mmol) was added and stirred at 0 °C for 15 minutes. The reaction was quenched by adding 1 mL of saturated aqueous NaHCO3. The reaction was extracted with EtOAc (3 x 25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by flash column chromatography. The purified product was triturated further with CH ³ CN and the solids collected by filtration to provide the title compound as a white solid. MS (ESI): mass calc. for C ²⁹ H ³² N ⁶ O ³ S, 544.2; m/z found, 545.3 [M+H]+.

[0638] Step D: 2-(( 1r,4r)-4- ( 2- ( 1- acetylpiperidin-4-yl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H )-yl)cyclohexyl)acetonitrile. The title compound (27.5 mg, 37% yield) was prepared using analogous conditions to those described in Example I, Step B using 2-((1r,4r)-4-(2-(1-acetylpiperidin- 4-yl)-6-(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (101 mg, 0.185 mmol) in place of 2- (1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide. The crude material was purified on a 12 gram silica gel column using 0 to 10% (2N NH3 in MeOH) in DCM to provide the title compound. MS (ESI): mass calc. for C ²³ H ²⁸ N ⁶ O, 404.2; m/z found, 405.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 5 II , 84 (s, 1H), 8.50 (s, 1H), 7.56-7.34 (m, 1H), 6.71 (d, J = 3.5 Hz, 1H), 4.63 -4.52 (m, 1H), 4.52 - 4.42 (m, 1H), 3.98 -3.88 (m, 1H), 3, 55 - 3.42 (m, 1H), 3.31 - 3.22 (m, 1H), 2.86 - 2.73 (m, 1H), 2.61 (d, J = 6.0 Hz, 2H), 2.47 - 2.38 (m, 2H), 2.05 (s, 3H), 2.03-1.96 (m, 3H), 1.96-1.80 (m, 5H) , 1.73-1.58 (m, 1H), 1.58-1.43 (m, 2H).

Reference Example 165 Synthesis and Characterization:

2-((1r,4r)-4-(2-((3-cyclopropyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)imidazo[4,5-a]pyrrolo [2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0639]

[0640] A solution of ( EZ)-N- (( 1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b ]pyridin-2-yl)methyl)-N'-hydroxycyclopropanecarboximidamide, as prepared in Example 110 (73 mg, 0.17 mmol), CDI (30 mg, 0.19 mmol) and THF (2 mL) were stirred for 1.5 h at 70 °C. The reaction was concentrated to dryness and the residue was purified by flash column chromatography and preparative HPLC using a Phenomenex Gemini 150 mm x 25 mm, 10 gm column (eluent: 23% to 53% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ) to provide the title compound (40 mg, 56% yield) as a white solid. MS (ESI): mass calc. for C ²² H ²³ N ⁷ O ² , 417.2; m/z found, 418.0 [M+H]+. 1H NMR (400 MHz, DMSO-afe): 511.93 (s, 1H), 8.55 (s, 1H), 7.54-7.46 (m, 1H), 6.79-6.71 ( m, 1H), 5.44 (s, 2H)), 4.67 -4.53 (m, 1H), 2.61 (d, J = 6.0 Hz, 2H), 2.43 - 2, 28 (m, 2H), 2.12-1.89 (m, 6H), 1.55-1.38 (m, 2H), 0.94-0.78 (m, 4H).

Reference Example 166 Synthesis and Characterization:

2- (( 1r,4r)-4- ( 2- ( 1 -(Oxazol-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[4,5-a]pyrrolo[2,3-b] pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0641]

[0642] Step A: 2-(( 1r,4r)-4- ( 2- ( 1 -(Oxazol-4-ylmethyl)-1 H-pyrazol-4-yl)-6-(phenylsulfonyl)imidazo[4, 5-d]pyrrolo[2,3-b]pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. To a 10 mL microwave vial was added 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-(1H-pyrazol-4-yl)imidazo[4,5-a]pyrrolo[ 2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (prepared in Example 123, Step A, 189 mg, 0.389 mmol) as a solid, followed by addition of DMF (0.833 mL), CS ^{2CO 3} (588 mg, 1.81 mmol) and 4-(bromomethyl)oxazole hydrobromide (189 mg, 0.778 mmol). The vial was sealed and the contents heated to 80 °C using a heating block for 4 h, then the reaction was allowed to slowly cool to room temperature. The reaction was added to 50 mL of water with stirring. The reaction was extracted with EtOAc (3 x 40 mL), dried over anhydrous MgSO4, and concentrated to dryness. The residue was purified by flash column chromatography (40 g SiO ² , 0-5% 2N NH3-MeOH/EA for 7 CV) to provide the title compound (116 mg, 53% yield) as a brown solid. dark. MS (ESI): mass calc. for C ²⁹ H ²⁶ N ⁸ O ³ S, 566.2; m/z found, 567.2 [M+H]+.

[0643] Step B: 2-((1r,4r)-4-(2-(1-(Oxazol-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[4,5-d]pyrrolo[ 2,3-b]pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. The title compound was prepared using analogous conditions to those described in Example 1, Step B. The residue was purified by flash column chromatography (24 g SiO ² , 0-10% 2N NH3-MeOH/EA for 12 CV ) to give the title compound (57 mg, 59% yield). MS (ESI): mass calc. for C ²³ H ²² N ⁸ O, 426.2; m/z found, 427.2 [M+h ]+. 1H NMR (500 MHz, DMSO-ds): 11.90 (s, 1H), 8.57 (s, 1H), 8.41 (d, J = 1.0 Hz, 1H), 8.34 ( d, J = 0.8 Hz, 1H)), 8.19 (q, J = 0.9 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.49 (t , J = 3.0 Hz, 1H), 6.75 (dd, J = 3.5, 1.9 Hz, 1H), 5.40 (s, 2H), 4.63 -4.44 (m, 1H), 2.58 (d, J = 6.3 Hz, 2H), 2.49-2.39 (m, 2H), 2.13-1.91 (m, 5H), 1.47-1 .30 (m, 2H).

Reference Example 167 Synthesis and Characterization:

2-(1 -((1r,4r)-4-(C¡anomethyl)cyclohex¡l)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl )-W-('( 1r,4r)-4- (trimethylsilyl)cyclohexyl)acetamide

[0644]

[0645] To a solution of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 sodium -yl)acetate (Intermediate 4, 60.0 mg, 0.170 mmol) and (1r,4r)-4-(trimethylsilyl)cyclohexanamine (prepared in Example 135, Step E, 43 mg, 0.25 mmol) in d Mf (3ml) PyBOP (174mg, 0.334mmol) and DIPEA (0.10ml, 0.58mmol) were added and stirred at room temperature for 18H. The reaction was concentrated to dryness, the residue was added water and the aqueous phase was extracted with EtOAc. The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 X 30 mm column (eluent: 10 - 90% CH ³ CN in H ² O, 0.1% TFA) twice to give the title compound ( 20 mg, 20% yield) as an off-white solid. MS (ESI): mass calc. for C27H38N6OS¡, 490.3; m/z found 491.4, [M+H]+. 1H NMR (400 MHz, CD ³ OD) 5 = 8.84 (s, 1H), 7.78 (d, J =3.0 Hz, 1H), 7.13 (br d, J =3.0 Hz , 1H), 4.99 (s, 2H), 4.71 (br s, 1H), 3.70 - 3.58 (m, 1H), 2.70 (s, 1H), 2.61 (br d, J =5.6 Hz, 3H), 2.30-2.13 (m, 5H), 2.12-2.00 (m, 2H), 1.94-1.77 (m, 2H) , 1.68-1.48 (m, 2H), 1.41-1.18 (m, 4H), 0.56 (br t, J =10.9 Hz, 1H), 0.00 (s, 9H).

Example 168 Synthesis and characterization:

2-((1r,4r)-4-(2-(1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)cyclohexyl)acetonitrile

[0646]

[0647] Step A: 2-(( 1r,4r)-4- ( 2- ( 1 -(2-Hydroxy-2-methylpropyl)piperidin-4-yl)-6-(phenylsulfonyl)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile. A solution of 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-(piperidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1( 6H)-//)cyclohexyl)acetonitrile, prepared in Example 165, Step B, (100 mg, 0.185 mmol), isobutylene oxide (0.165 mL, 1.86 mmol), and CS ² CO ³ (212 mg, 0.649 mmol )) in CH ³ CN (1 mL) was heated at 130 °C in the microwave for 1 hour. The reaction was diluted with water (25 mL) and CH ² Cl ² (5 mL), extracted with EtOAc (3 x 25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to provide the compound of the title as a transparent liquid. oil, which was used without further purification. MS (ESI): mass calc. for C ³¹ H ³⁸ N ⁶ O ³ S, 574.3; m/z found, 575.2 [M+H]+.

[0648] Step B: 2-((1r,4r)-4-(2-(1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)imidazo[4,5-a]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile. The title compound (30.3 mg, 38% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2-((1r,4r)-4-(2-(1-(2 -Hydroxy-2-methylpropyl)piperidin-4-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (106 mg , 0.184 mmol) instead of 2-(1-((1r,4r)-4-(C¡anomethyl)c¡clohex¡l)-6-(phen¡ísulfon¡l)-1,6-dihydroimidazo[4 ,5-d]pyrrolo[2,3-b]pyridin-2-yl)-W-(2-hydroxy-2-methylpropyl)acetamide. The crude material was purified on a 12 gram silica gel column using 0 to 10% (2N NH3 in MeOH) in DCM to provide the title compound. MS (ESI): mass calc. for C ²⁵ H ³⁴ N ⁶ O, 434.3; m/z found, 435.3 [M+H]+. 1H NMR (400 MHz, DMSO-ds): 511.82 (s, 1H), 8.50 (s, 1H), 7.49-7.42 (m, 1H), 6.70 (d, J = 3.5 Hz, 1H), 4.61 -4.40 (m, 1H), 4.08 (s, 1H), 3.12 - 2.98 (m, 3H), 2.60 (d, J = 6.0 Hz, 2H), 2.39-2.30 (m, 4H), 2.25 (s, 2H)), 2.07-1.92 (m, 4H), 1.94-1 .85 (m, 3H), 1.85-1.76 (m, 2H), 1.58-1.41 (m, 2H), 1.11 (s, ^6H ).

Reference Example 169 Synthesis and Characterization:

2-((1r,4r)-4-(2-(4-(4-Ethynylbenzoyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile

[0649]

[0650] Step A: 2-((1r,4r)-4-(2-(4-(4-Formylbenzoyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b/pyridin-1 ( 6H)-yl)cyclohexyl)acetonitrile. 2-((1r,4r)-4-(2-(4-(4-(Hídrox¡met¡l)benzo¡l)fen¡l)¡m¡dazo[4,5-a(]p ¡rro¡o[2,3-b]p¡r¡d¡n-1 (6H)-yl)cyclohexyl)acetonitrile, as prepared in Example 121, (243 mg, 0.496 mmol) was dissolved in CH ² CL (13 mL) and DMF (4 mL) with gentle warming with a heat gun then cooled to room temperature Dess-Martin periodinane (234 mg, 0.550 mmol) was then added in two 117 mg portions After that last addition, the reaction was stirred for a further 15 minutes.The reaction was concentrated to dryness and the residue was purified by flash column chromatography to give the title compound (165 mg, 68.2% yield) as a light tan solid MS (ESI): mass calcd for C ³⁰ H ²⁵ N ⁵ O ² , 487.2, m/z found, 488.2 [M+H]+.

[0651] Step B: dimethyl (2-oxo-1-(1A4,2A4-triaza-1,2-dien-1-ylidene)propyl)phosphonate. To a solution of dimethyl (2-oxopropyl)phosphonate (1000 mg, 6.02 mmol) in CH ³ CN (3.5 mL) was added tosyl azide (1.108 mL, 7.224 mmol) at room temperature. K ² CO ³ (1.165 g, 8.428 mmol)) was then added and the reaction stirred for 2 h. Next, 15 mL of saturated aqueous NH4Cl was added and the reaction was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness. The material was dissolved in 6 ml of MeCN to obtain an approximately 1 M solution, which was used as is in the next reaction.

[0652] Step C: 2-((1r,4r)-4-(2-(4-(4-Ethynylbenzoyl)phenyl)imidazo[4,5-c/]pyrrolo[2,3-b]pyridin-1 (6H)-//)cyclohexyl)acetonitrile. 2-((7r,4r)-4-(2-(4-(4-Formylbenzoyl)phenyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile (165 mg, 0.338 mmol) was dissolved in MeOH (20 mL) and dimethyl(2-oxo-1-(1A4,2A4-triaza-1,2-dien-1-ylidene)propyl)phosphonate solution was added (1M in CH ³ CN, 1.015 mL, 1.015 mmol). To this solution was added K ² CO ³ (234 mg, 1.69 mmol) and the reaction stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO3 (2 mL), extracted with EtOAc (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude material was purified on a 24 gram silica gel column using 0-10% MeOH in DCM to provide the title compound (33 mg, 20% yield) as a tan solid. MS (ESI): mass calc. for C ³¹ H ²⁵ N ⁵ O, 483.2; m/z found, 484.2 [M+H]+. 1H NMR (400 MHz, CDCb): 512.37 (s, 1H), 8.96 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.90 - 7.74 (m, 4H), 7.64 (d, J = 8.2 Hz, 2H), 7.59 - 7.52 (m, 1H), 6.82 -6.69 (m, 1H), 4, 65 -4.43 (m, 1H), 3.30 (s, 1H), 2.77 - 2.54 (m, 2H)), 2.41 (d, J = 6.0 Hz, 2H), 2.23-2.02 (m, 5H), 1.50-1.29 (m, 2H).

Reference Example 170 Synthesis and Characterization:

2-((7r,4r)-4-(2-(4-(4-Ethynylbenzoyl)phenethyl)imidazo[4,5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl )acetonitrile

[0653]

[0654] Step A: (E)-3-(4-(4-Bromobenzoyl)phenyl)acrylaldehyde. Pd(OAc) 2 (0.033 g, 0.15 mmol) was added to a solution of 4,4'-dibromobenzophenone (1.00 g, 2.94 mmol), acrolein (0.247 g, 4.41 mmol), carbonate potassium chloride (0.813 g, 5.88 mmol), benzyltriethylammonium chloride (0.670 g, 2.94 mmol), 4A molecular sieves (1 g) and dry DMF (14 mL) under N ² and the reaction mixture was quenched. stirred for 4 h at 60 °C in a microwave tube. The solution was filtered, the filtrate was diluted with water (100ml) and extracted with ethyl acetate (100ml x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to provide the title compound as a yellow solid. MS (ESI): mass calc. for C ¹⁶ HnBrO ² , 313.99; m/z found, 317.2 [M+H]+.

[0655] Step B: (4-bromophenyl)(4-(3-hydroxypropyl)phenyl)methanone. A solution of (E)-3-(4-(4-bromobenzoyl)phenyl)acrylaldehyde (864 mg, 2.74 mmol), Pt/C (160 mg, 5%) and ethyl acetate (40 mL) was stirred for 12 hrs. at 15 °C under H ² . TLC showed a small amount of (E)-3-(4-(4-bromobenzoyl)phenyl)acrylaldehyde remaining, so the reaction mixture was filtered and more Pt/C (100 mg) was added and the mixture reaction was stirred for 6 h at 15 °C under H ² . The solution was filtered and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography to provide the title compound (266 mg, 30% yield) as a white solid. 1H NMR (400 MHz, CDCl3) 7.71 (d, J =8.0 Hz, 2H), 7.69-7.59 (m, 4H), 7.34-7.29 (m, 1H), 7.38 - 7.25 (m, 1H), 3.70 (t, J =6.4Hz, 2H), 2.81 (t, J =7.6Hz, 2H), 1.99-1 .86 (m, 2H).

[0656] Step C: 3-(4-(4-Bromobenzoyl)phenyl)propanal. Dess-Martin periodinan (424 mg, 1.00 mmol) was added to a solution of (4-bromophenyl)(4-(3-hydroxypropyl)phenyl)methanone (266 mg, 0.833 mmol) and CH ² CL (14 mL ) at 0 °C and stirred overnight at 15 °C. TLC showed some (4-bromophenyl)(4-(3-hydroxypropyl)phenyl)methanone remaining, so more Dess-Martin periodinan (134 mg, 0.316 mmol) was added to the reaction mixture and stirred. for 3 more h. at 15°C. The reaction was quenched with saturated NaHCO3 and saturated Na2S2O3 (1: 1.30 mL) and the reaction stirred for 30 minutes at 15 °C. The reaction was extracted with CH ² Cl (30 mL), the organic layer washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 to 12:88) to give the title compound (120 mg, 45% yield) as a white solid. 1H NMR (400 MHz, CDCl3): 59.84 (s, 1H), 7.75-7.69 (m, 2H), 7.68-7.60 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 3.09-2.99 (m, 2H), 2.89-2.80 (m, 2H).

[0657] Step D: 2-((1r,4r)-4-(2-(4-(4-Bromobenzoyl)phenethyl)-6-(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3- b]pyridin-1( 6H)-yl )cyclohexyl)acetonitrile. A solution of 3-(4-(4-bromobenzoyl)phenyl)propanal (303 mg, 0.956 mmol), 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo [2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (intermediate 1.280 mg, 0.637 mmol), sodium hydrosulfite (555 mg, 3.19 mmol), dMsO (2.5 mL), MeOH (7.5 mL)), and water (5 mL) was stirred for 7 h at 100 °C in a microwave tube. The mixture was concentrated to dryness, washed with water (10ml X 3), filtered and dried under reduced pressure. The residue was purified by flash column chromatography to give the title compound (360 mg, 74% of performance). MS (ESI): mass calc. for C37H32BrN5Ü3S, 705.14; m/z found, 707.9 [M+H]+.

[0658] Step E: 2-((7r,4r,)-4-(6-(Fen¡lsulfon¡l)-2-(4-(4-((trimeth¡ls¡l¡l)et¡n ¡l)benzo¡l)phenet¡l)¡m¡m¡dazo[4,5-d]p¡rrolo[2,3-b]p¡rid¡n-1(6H)-¡l)c¡clohexyl) acetone it. To a solution of 2- (( 1r,4r)-4- ( 2- ( 4- ( 4- bromobenzo¡l)pheneth¡l)-6-(phen¡lsulfon¡l)¡m¡dazo[4,5-d]p¡rrolo[2,3-b]p¡r¡d¡n-1 (6H )-¡l)c¡clohex¡l)aceton¡tr¡l (250 mg, 0.35 mmol), CuI (8.1 mg, 0.042 mmol), tetrak¡s(tr¡fen¡lfosf¡na)palad ¡o(0) (82 mg, 0.071 mmol), triethylamin (430 mg, 4.25 mmol) and DMF (6 mL) under Ar in a microwave vessel. The container was covered and irradiated at 110 °C for 40 minutes. The reaction mixture was concentrated to dryness and purified by flash column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 to 42:58) to provide the compound of qualification. MS (ESI): mass calc. for C42H41N5Ü3SS¡, 723.27; m/z found, 724.3 [M+H]+.

[0659] Step F: 2-((1r,4r)-4-(2-(4-(4-Et¡n¡lbenzo¡l)fenet¡l)¡m¡dazo[4,5-a(] p¡rrolo[2,3-b]p¡r¡d¡n-1 (6H)-//)c¡clohex¡l)aceton¡tr¡le The title compound (50 mg, 43% yield ¡mento) was prepared as a light yellow solid using analogous conditions to those described in Example 1, Step B using 2-((1r,4r)-4-(6- (phenylsulfonyl)-2-(4-(4-((tr'imethylsilyl)ethynyl)benzoyl)phenethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H) -yl)cyclohexyl)acetonitrile (220 mg, 0.220 mmol) in place of 2-(1 -((1r,4r)-4-(cyanomethyl)c¡clohex¡l)-6-(phenylsulfon ¡l)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyr'idin-2-yl)-N-(2-hidrox¡-2-methylpropyl) )acetamide The compound was purified primarily by flash column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 to 0:100). It was further purified by preparative HPLC with a Boston Green ODS column of 150 mm x 30 mm, 5 gm (eluent: 30% to 60% (v/v) CH ³ CN and H ² O with 0.1% TFA) MS (ESI): mass calcd for C ³³ H ²⁹ N ⁵ O, 51 1.2; m/z found, 512.0 [M+H]+. 1H NMR (400MHz, CDCh): 510.59 (s, 1H), 8.81 (s, 1H), 7.78-7.71 (m, 4H), 7.59 (d, J = 8.0 Hz, 2H), 7.47 - 7.35 (m, 3H), 6.69 (s, 1H), 4.46 - 4.17 (m, 1H), 3.49 - 3.36 (m, 2H), 3.35 - 3.27 (m, 2H), 3.25 (s, 1H), 2.69 - 2.47 (m, 2H), 2.44 (d, J = 6.0 Hz , 2H), 2.23 - 2.12 (m, 2H), 2.11 - 2.02 (m, 1H), 1.97-1.82 (m, 2H), 1.54-1.37 (m, 2H).

Reference example 171 Synthesis and characterization:

1 -((1 -((1r,4r)-4-(c¡anomet¡l)c¡clohex¡l)-1,6-d¡h¡d¡dro¡m¡dazo[4,5-d]p ¡rrolo[2,3-b]p¡r¡d¡n-2-¡l)met¡l)-3-¡soprop¡lurea

[0660]

[0661] Step A: 1-((1-((1r,4r)-4-(C¡anomet¡l)c¡clohex¡l)-6-(phenylsulfon¡l)-1,6-d ¡h¡dro¡m¡dazo[4,5-c/]p¡rrolo[2,3-b]p¡r¡d¡n-2-¡l)methyl)-3-¡soprop¡lurea . A solution of 2-((1r,4r)-4-(2-(am¡nomethyl)-6-(fen¡lsulfon¡l)¡m¡dazo[4,5-d]p¡rrolo [2,3-b]p¡r¡d¡n-1 (6H)-¡l)c¡clohex¡l)aceton¡trilo (¡intermediate 5, 136 mg, 0.242 mmol), 2- Isocyanatopropane (110 mg, 1.29 mmol) and triethylamine (0.168 mL, 1.21 mmol) in DMF (1.5 mL) was stirred at room temperature for 24 h. The reaction was concentrated to dryness and the residue was purified by flash column chromatography to provide the title compound (200 mg). MS (ESI): mass calc. for C ²⁷ H ³¹ N ⁷ O ³ S, 533.2; m/z found, 534.3 [M+H]+.

[0662] Step B: 1 -((1 -((1r,4r)-4-(C¡anomethyl)c¡clohex¡l)-1,6-dihydroimidazo[4,5-ó]pyrrolo[2 ,3-b]pyridin-2-yl)methyl)-3-isopropyllurea. A mixture of 1-((1-((1r,4r)-4-(cyanomethyl)c¡clohex¡l)-6-(phenylsulfon¡l)-1,6-d¡h¡ dro¡m¡dazo[4,5-d]p¡rrolo[2,3-b]p¡r¡d¡n-2-¡l)methyl)-3-¡soprop¡lurea (200 mg, 0.370 mmol), 3M NaOH (aq) (0.25 mL, 0.75 mmol), THF (1 mL) and MeOH (1 mL) were stirred at RT for 15 h and concentrated in vacuo. The residue was partitioned between CH ² Cl ² and water. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash column chromatography (2-10% MeOH in CH ² Cl ² ) to give the title compound as a white solid (54 mg, 37%). MS (ESI): mass calc. for C ²¹ H ²⁷ N ⁷ O, 393.2; m/z found, 394.2 [M+H]+. 1H NMR (400 MHz, CDCh) 512.19 (br s, 1H), 8.72 (s, 1H), 7.44 (t, J = 2.8 Hz, 1H), 6.67 (br s, 2H), 5.29 (br s, 1H), 4.82 (d, J = 5.6 Hz, 2H), 4.66 (br s, 1H), 3.95 - 3.83 (m, 1H ), 2.74 (br s, 1H), 2.46 (br s, 2H), 2.40 - 2.25 (m, 2H), 2.08 (br d, J = 11.6 Hz, 2H ), 1.97 (br s, 2H), 1.43-1.25 (m, 2H), 1.07 (d, J = 6.6 Hz, 6H).

Reference example 172 Synthesis and characterization:

1-((1r,4r)-4-(C¡anomet¡l)c¡clohex¡l)-N-¡soprop¡l-1,6-d¡h¡d¡ro¡m¡dazo[4,5- d]p¡rrolo[2,3-b]p¡r¡d¡na-2-carboxam¡da

[0663]

[0664] The title compound (28 mg, 38% yield) was prepared using analogous conditions to those described in Example 50, Step A using isopropylamine in place of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²⁰ H ²⁴ N ⁶ O, 364.2; m/z found, 365.2 [M+H]+. 1H NMR (500 MHz, CDCls) 510.22 (s, 1H), 8.82 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.45 (dd, J = 3.5, 2.6 Hz, 1H), 6.81 (dd, J = 3.6, 2.0 Hz, 1H), 6.29 - 5.84 (m, 1H), 4.41 -4 .17 (m, 1H), 2.77 - 2.52 (m, 2H), 2.40 (d, J = 6.6 Hz), 2H), 2.23 - 2.00 (m, 5H) , 1.58-1.43 (m, 2H), 1.34 (d, J = 6.6 Hz, 6H).

Reference Example 173 Synthesis and Characterization:

1-((7r;4r,)-4-(cyanomethyl)cyclohexyl)-W-(3-methoxypropyl)-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2 -carboxamide

[0665]

[0666] The title compound (30 mg, 37% yield) was prepared using analogous conditions to those described in Example 50, Step A using 3-methoxypropan-1-amine in place of 3-phenylpyrroline-3-ol. MS (ESI): mass calc. for C ²¹ H ²⁶ N ⁶ O ² , 394.2; m/z found, 395.2 [M+H]+. 1H NMR (500 MHz, CDCla): 11.38 (s, 1H), 8.85 (s, 1H), 8.31-8.10 (m, 1H), 7.59-7.35 (m , 1H), 6.90 -6.71 (m, 1H), 6.31 - 5.63 (m, 1H), 3.77 - 3.47 (m, 4H), 3.41 (s, 3H ), 2.78 - 2.51 (m, 2H), 2.40 (d, J = 6.6 Hz, 2H), 2.26 - 2.01 (m, 5H), 2.02-1, 88 (m, 2H), 1.61 -1.38 (m, 2H).

Reference Example 174 Synthesis and Characterization:

1-((ir,4r,)-4-(cyanomethyl)cyclohexyl)-N-(cyclopropylmethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide

[0667]

[0668] The title compound (17 mg, 55% yield) was prepared using analogous conditions to those described in Example 50, Step A and using cyclopropylmethylamine in place of 3-phenylpyrroline-3-ol. MS (ESI): mass calc. for C ²¹ H ²⁴ N ⁶ O, 376.2; m/z found, 377.2 [M+H]+. 1H NMR (500 MHz, CDCh) 510.52 (s, 1H), 8.84 (s, 1H), 7.93 (t, J = 5.7 Hz, 1H), 7.66 - 7.40 ( m, 1H), 6.82 (d, J = 3.5 Hz, 1H), 6.33 - 5.84 (m, 1H), 3.35 (dd, J = 7.2, 5.7 Hz , 2H), 2.73 - 2.55 (m, 2H), 2.40 (d, J = 6.6 Hz, 2H), 2.25 - 2.00 (m, 5H), 1.57- 1.41 (m, 2H), 1.18-1.03 (m, 1H), 0.69-0.56 (m, 2H), 0.39-0.25 (m, 2H).

E x a m p le 175 S in te sis an d c a r c t e r iz a tio n:

1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-N-cyclopropyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carboxamide

[0669]

[0670] The title compound (34 mg, 47% yield) was prepared using analogous conditions to those described in Example 50, Step A and using cyclopropylamine in place of 3-phenylpyrrolin-3-ol MS (ESI): mass calculated for C ²⁰ H ²² N ⁶ O, 362.19; m/z found, 363.2 [M+H]+. 1H NMR (500 MHz, CDCls) 510.77 (s, 1H), 8.81 (s, 1H), 7.90 (d, J = 3.5 Hz, 1H), 7.59-7.39 ( m, 1H), 6.96 - 6.71 (m, 1H), 6.43 - 5.80 (m, 1H), 3.03 - 2.80 (m, 1H), 2.74 - 2, 46 (m, 2H), 2.40 (d, J = 6.6 Hz, 2H), 2.25-2.00 (m, 5H), 1.61-1.38 (m, 2H), 1 0.05 - 0.86 (m, 2H), 0.81 - 0.62 (m, 2H).

Reference Example 176 Synthesis and Characterization:

2-((ir,4r,)-4-(2-(4-methoxypiperidine-1-carbonyl)imidazo[4,5-a(|pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile

[0671]

[0672] The title compound (30 mg, 35% yield) was prepared using analogous conditions to those described in Example 50, Step A, and using 4-methoxypiperidine in place of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²³ H ²⁸ N ⁶ O ² , 420.2; m/z found, 421.3 [M+H]+. 1H NMR (500 MHz, CDCla) 5 12.76 - 12.12 (m, 1H), 8.81 (s, 1H), 7.64 (d, J = 3.3 Hz, 1H), 6.86 (d, J = 3.4 Hz, 1H), 5.35 - 5.23 (m, 1H), 4.79 -4.59 (m, 1H), 4.10 - 3.89 (m, 1H ), 3.89 - 3.68 (m, 2H), 3.50 (s, 4H), 2.55 - 2.36 (m, 4H), 2.23 - 2.09 (m, 5H), 2.11-1.91 (m, 2H), 1.91-1.69 (m, 2H), 1.59-1.38 (m, 2H).

Reference Example 177 Synthesis and Characterization:

1-(1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-carbonyl)piperidine-4-carbonitrile [0673]

[0674] The title compound (25 mg, 30% yield) was prepared using analogous conditions to those described in Example 50, Step A and using piperidine-4-carbonitrile in place of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C23H25N7O, 415.2; m/z found, 416.2 [M+H]+. 1H NMR (400 MHz, CDCls) 510.22 (s, 1H), 8.75 (s, 1H), 7.46-7.31 (m, 1H), 6.78-6.60 (m, 1H ), 4.84 -4.51 (m, 1H)), 4.01 - 3.63 (m, 4H), 3.06 - 2.88 (m, 1H), 2.47 - 2.29 ( m, 4H), 2.16-1.81 (m, 9H), 1.52-1.31 (m, 2H).

Re fere n ce e xample 178 S in te sis an d c a c ter iz a tio n:

1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-W-(tetrahydro-2H-pyran-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b ]pyridine-2-carboxamide [0675]

[0676] The title compound (40 mg, 48% yield) was prepared using analogous conditions to those described in Example 50, Step A and using tetrahydro-2H-pyran-4-amine_in place of 3-phenylpyrroline-3- ol. MS (ESI): mass calc. for C ²² H ²⁶ N ⁶ O ² , 406.2; m/z found, 407.2 [M+H]+. 1H NMR (500 MHz, CDCls) 510.72 (s, 1H), 8.77 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 3.5 Hz, 1H), 6.75 (d, J = 3.6 Hz, 1H), 6.36 - 5.51 (m, 1H), 4.36 - 3.79 (m, 3H), 3.56 - 3.36 (m, 2H), 2.75 - 2.46 (m, 2H), 2.33 (d, J = 6.6 Hz, 2H), 2.23-1.92 ( m, 7H), 1.76-1.53 (m, 2H), 1.55-1.24 (m, 2H).

Reference Example 179 Synthesis and Characterization:

1 -((ír,4r,)-4-(Cyanomethyl)cyclohexyl)-W-^1 -methoxypropan-2-yl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b] pyridine-2-carboxamide [0677]

[0678] The title compound (21 mg, 16% yield) was prepared using analogous conditions to those described in Example 50, Step A and using 1-methoxypropan-2-amine in place of 3-phenylpyrrolin-3-ol . MS (ESI): mass calc. for C ²¹ H ²⁶ N ⁶ O ² , 394.2; m/z found, 395.2 [M+H]+. 1H NMR (500 MHz, CDCla): 59.75 (s, 1H), 8.82 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.47-7.37 (m, 1H), 6.90 -6.76 (m, 1H), 6.25-5.75 (m, 1H), 4.43 -4.23 (m, 1H), 3.51 (dd , J = 4.8, 1.9 Hz, 2H), 3.43 (s, 3H), 2.76 - 2.54 (m, 2H), 2.40 (d, J = 6.6 Hz, 2H), 2.23-2.01 (m, 5H), 1.58-1.42 (m, 2H), 1.36 (d, J =6.8 Hz, 3H). Reference Example 180 Synthesis and Characterization:

2-((7r,4r)-4-(2-(morpholine-4-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0679]

[0680] The title compound (21 mg, 26% yield) was prepared using analogous conditions to those described in Example 50, Step A using 4-_morpholine in place of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²¹ H ²⁴ N ⁶ O ² , 392.2; m/z found, 393.2 [M+H]+. 1H NMR (500 MHz, CDCla) 5 12.31 (s, 1H), 8.83 (s, 1H), 7.66 (d, J = 3.5 Hz, 1H), 7.01 -6.56 (m, 1H), 4.95 - 4.64 (m, 1H), 3.99 - 3.67 (m, 8H), 2.61 - 2.35 (m, 4H), 2.31-1 .91 (m, 5H), 1.68-1.34 (m, 2H).

Reference Example 181: Synthesis and Characterization

2-((1r,4r)-4-(2-(4-Hydroxypiperidine-1-carbonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) acetonitrile

[0681]

[0682] The title compound (35 mg, 42% yield) was prepared using analogous conditions to those described in Example 50, Step A and using 4-hydroxypiperidine in place of 3-phenylpyrrolin-3-ol. MS (ESI): mass calc. for C ²² H ²⁶ N ⁶ O ² , 406.2; m/z found, 407.2 [M+H]+. 1H NMR (500 MHz, CDCla) 11.09 (s, 1H), 8.82 (s, 1H), 7.46 (dd, J = 3.6, 1.7 Hz, 1H), 6.74 (d, J = 3.4 Hz, 1H), 4.81 - 4.59 (m, 1H), 4.36 -4.19 (m, 1H), 4.16 -4.03 (m, 1H ), 4.01 - 3.86 (m, 1H), 3.64 - 3.43 (m, 2H), 2.58-1.92 (m, 12H), 1.82-1.61 (m , 2H), 1.57-1.34 (m, 2H).

Reference Example 182 Synthesis and Characterization:

Ethyl 2-(4-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]]pyridin-2- yl)-1 H-pyrazol-1 -yl)acetate [0683]

[0684] Step A: To a 10 mL microwave vial was added 2-((1r,4r,)-4-(6-(phenylsulfonyl)-2-(1H-pyrazol-4-yl)imidazo[4, 5-a]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile, as prepared in Example 123, Step A (203 mg, 0.418 mmol) followed by ACN (1.00 mL ), cesium carbonate (440 mg, 1.35 mmol) and ethyl bromoacetate (0.10 mL, 0.884 mmol). The vial was sealed and heated at 80 °C for 2 h. The contents were added in water/brine (1:1) and then extracted with CH ² Cl ² (2 x 40 mL). The organic extracts were dried with Na2SO4 and then concentrated to dryness. The crude material was purified by flash column chromatography (40 to 100% EA/hex) to provide the title compound (122 mg, 51%) as a colorless residue. 1H NMR (500 MHz, CDCla) 58.89 (s, 1H), 8.29-8.19 (m, 2H), 7.97 (d, J = 0.7 Hz, 1H), 7.86 ( d, J = 4.0 Hz, 1H), 7.80 (d, J = 0.7 Hz, 1H), 7.62 - 7.53 (m, 1H), 7.53 - 7.43 (m , 2H), 6.86 (d, J = 4.1 Hz, 1H), 5.02 (s, 2H), 4.72 -4.57 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.52 - 2.37 (m, 4H), 2.23 - 2.13 (m, 2H), 2.10-1.97 (m, 2H), 1.49 -1.35 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0685] Step B: 2-(4-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine Ethyl -2-yl)-1 H -pyrazol-1 -yl)acetate. The title compound was prepared using analogous conditions to those described in Example 123, step C (16.0 mg, 17% yield). The residue was purified by flash column chromatography (24 g SiO ² , 0 5% 2n NH 3 -MeOH/EA) to give the title compound MS (ESI): mass calculated. for C ²³ H ²⁵ N ⁷ O ² , 431.2; m/z found, 432.2 [M+H]+. 1H NMR (500 MHz, DMSO-ds) 511.91 (s, 1H), 8.58 (s, 1H), 8.33 (s, 1H), 7.95 (s, 1H), 7.50 ( t, J = 3.1 Hz, 1H), 6.76 (dd, J = 3.4, 1.8 Hz, 1H), 5.21 (s, 2H), 4.68 -4.45 (m , 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.58 (d, J = 6.2 Hz, 2H), 2.53 - 2.40 (m, 2H), 2 .14-1.90 (m, 5H), 1.48-1.30 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H).

Reference Example 183 Synthesis and Characterization:

2-((1r,4r)-4-(2-(2,4-dimethyloxazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile

[0686]

[0687] Step A: 2-((7r,4r)-4-(2-(2,4-dimethyloxazol-5-yl)-6-(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3 -b]pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino)cyclohexyl)acetonitrile (Intermediate 1, 192 mg, 0.437 mmol) and 2,4-dimethyloxazole-5-carbaldehyde (140 mg, 1.07 mmol) as solids. DMSO (2.20 ml), MeOH (2.20 ml) and distilled water (1.10 ml) were then added. Sodium hydrosulfite (229 mg, 1.32 mmol) was then added as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100 °C for 1 h. The reaction was cooled to room temperature and poured into 30 mL of water, resulting in the formation of a precipitate. The mixture was stirred for 15 minutes and then the solids were collected by filtration and dried under high vacuum for 1 h to provide the title compound (169 mg, 75.2% yield). MS (ESI): mass calc. for C ²⁷ H ²⁶ N ⁶ O ³ S, 514.2; m/z found, 515.2 [M+H]+.

[0688] Step B: 2-((1r,4r)-4-(2-(2,4-dimethyloxazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile. The title compound (16.3 mg, 13% yield) was prepared using analogous conditions to those described in Example 2, Step B using 2-((1r,4r)-4-(2-(2,4- dimethyloxazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (169 mg, 0.33 mmol) in place of 2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-W -(2-hydroxy-2-methylpropyl)acetamide. The residue was purified by flash column chromatography (12 g SiO ² , 0-8% 2N NH ³ -MeOH/EA over 12 CV) to provide the title compound. MS (ESI): mass calc. for C ²¹ H ²² N ⁶ O, 374.2; m/z found, 375.2 [M+H]+. 1H NMR (500 MHz, DMSO-afe) 512.01 (s, 1H), 8.65 (s, 1H), 7.53 (d, J = 3.4 Hz, 1H), 6.80 (d, J = 3.5 Hz, 1H), 4.70 -4.54 (m, 1H), 2.55 (d, J = 6.2 Hz, 2H), 2.52 (s, 3H), 2, 39-2.29 (m, 5H), 2.08-1.86 (m, 5H), 1.38 (tt, J=13.6, 7.4 Hz, 2H).

Reference Example 184 Synthesis and Characterization:

2-((1r,4r)-4-(2-(2,4-dimethylthiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile

[0689]

[0690] Step A: 2-((1r,4r)-4-(2-(2,4-dimethylthiazol-5-yl)-6-(phenylsulfonyl)imidazo[4,5-a]pyrrolo[2,3 -b]pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. To a 20 mL microwave vial was added 2-((1r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino)cyclohexyl)acetonitrile (Intermediate 1, 201 mg, 0.457 mmol) and 2,4-dimethyl-1,3-thioxazole-5-carbaldehyde (158 mg, 1.09 mmol) as solids. DMSO (2.10 ml), MeOH (2.10 ml) and distilled water (1.10 ml) were then added. Sodium hydrosulfite (250 mg, 1.44 mmol) was then added as a solid and the vial was sealed. The vial was placed on a heating block preheated to 100°C for 1 hour. The reaction was cooled to room temperature and poured into 60 mL of water, resulting in the formation of a precipitate. The mixture was stirred for 15 minutes and then the solids were collected by filtration and dried under high vacuum for 1 h to provide the title compound (205 mg, 84% yield) as a pale yellow powder. MS (ESI): mass calc. for C ²⁷ H ²⁶ N ⁶ O ² S ² , 530.2; _m/z found, 531.1 [M+H]+.

[0691] Step B: 2-((1r,4r)-4-(2-(2,4-dimethylthiazol-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile. The title compound (33.0 mg, 21% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2-((1r,4r)-4-(2-(2,4- dimethylthiazol-5-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridinl(6H)-yl)cyclohexyl)acetonitrile (205 mg, 0.39 mmol) in place of 2-(1 -((7r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2- yl)-W-(2-hydroxy-2-methylpropyl)acetamide. The residue was purified by flash column chromatography (24 g SiO ² , 0-10% 2N NH 3 -MeOH/EA) to provide the title compound. MS (ESI): mass calc. for C ²¹ H ²² N ⁶ S, 390.2; m/z found, 391.2 [M+H]+. 1H ^r M ⁿ (500 MHz, DMSO-afe) 5 12.00 (s, 1H), 8.64 (s, 1H), 7.53 (d, J = 3.4 Hz, 1H), 6.78 (d, J = 3.5 Hz, 1H), 4.50 - 4.10 (m, 1H), 2.73 (s, 3H), 2.53 (d, J = 6.2 Hz, 2H), 2.45 - 2.34 (m, 2H), 2.32 (s, 3H), 2.09-1.85 (m, 5H), 1.40-1.23 (m, 2H) .

Reference Example 185 Synthesis and Characterization:

2-(4-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)- 1 AV-pyrazol-1 -yl)-N-cyclopropylacetamide

[0692]

[0693] Step A: 2-(4-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazO4,5-a]pyrrolo[2,3 -b]pyridin-2-yl)-1H-pyrazol-1-yl)-N-cyclopropylacetamide. To a 10 mL microwave vial was added 2-((1r,4r)-4-(6-(phenylsulfonyl)-2-(1H-pyrazol-4-yl)imidazo[4,5-d]pyrrolo[ 2,3-¿>]pyridin-1(6H)-yl)cyclohexyl)acetonitrile, as prepared in Example 123, Step A (197 mg, 0.406 mmol) as a solid, followed by addition of CH ³ CN ( 1 mL), CS ² CO ³ (423 mg, 1.81 mmol) and 2-bromo-N-cyclopropylacetamide (141 mg, 0.792 mmol). The vial was sealed and the contents heated to 80 °C using a heating block for 1 h, then the reaction was cooled to room temperature. The reaction was diluted with CH ² Cl ² (30 ml) and poured into water (25 ml). The organic layer was removed and the aqueous layer was extracted with CH ² Cl ² (30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by flash column chromatography (24 g SiO ² , 0-10% 2N NH 3 -MeOH/EA) to provide the title compound (103 mg, 43% yield) as a dark brown solid. No mass detectable by ESI MS.

[0694] Step B: 2-(4-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)-1 H-pyrazol-1-yl)-N-cyclopropylacetamide. The title compound (6.4 mg, 8% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2-(4-(1-((1r,4r)-4-(Cyanomethyl )cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)-N-cyclopropylacetamide ( 103 mg, 0.18 mmol) instead of 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo [2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. The residue was purified by flash column chromatography (12 g SiO ² , 0-10% 2N NH ³ -MeOH/EA over 12 CV) to provide the title compound. MS (ESI): mass calc. for C ²⁴ H ²⁶ N ⁸ O, 442.2; m/z found, 443.3 [M+H]+. 1H NMR (500 MHz, DMSO-ds): 11.90 (s, 1H), 8.57 (s, 1H), 8.35 (d, J = 4.2 Hz, 1H), 8.26 ( d, J = 0.8 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.50 (t, J = 3.0 Hz, 1H), 6.80 -6, 72 (m, 1H), 4.86 (s, 2H), 4.68 -4.49 (m, 1H), 2.75 - 2.63 (m, 1H), 2.57 (d, J = 6.4 Hz, 2H), 2.50-2.40 (m, 2H), 2.18-1.92 (m, 5H), 1.50-1.33 (m, 2H), 0.74 -0.62 (m, 2H), 0.56 - 0.42 (m, 2H).

Reference Example 186 Synthesis and Characterization:

2-((1r,4r)-4-(2-(2-aminopyridin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-/'/) cyclohexyl)acetonitrile

[0695]

[0696] The title compound (27 mg, 15% yield) was prepared using conditions analogous to Example 51 and using 2-aminonicotinaldehyde in place of aminopyrimidine-5-carbaldehyde. MS (ESI): mass calc. for C ²¹ H ²¹ N ⁷ , 371.2; m/z found, 372.2 [M+H]+. 1H NMR (500 MHz, methanol-d4) 58.65 (s, 1H), 8.27-8.10 (m, 1H), 7.80-7.62 (m, 1H), 7.59-7 .41 (m, 1H), 7.00 - 6.80 (m, 2H), 4.39 - 4.22 (m, 1H), 2.74 - 2.40 (m, 4H), 2.20 -1.92 (m, 5H), 1.44-1.21 (m, 2H).

Reference Example 187 Synthesis and Characterization:

2 -( (1 r ,4 r ) -4 -(2 -(1 -(2 -H id ro x i-2 -met ilp ro p il) -1 H -p ira zo l-4 - il) im id azo [4 ,5 -d ]p ir ro lo [2 ,3 -b ]p ir id in -1 (6 H ) - il) c ic lo hexyl)ace to n it ri lo

[0697]

[0698] Step A: 2-(( 1r,4r)-4-(2-(1 -(2-Hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)-6-(phenylsulfonyl)imidazo[ 4,5-a(|pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile Into a 10 mL microwave vial was charged 2-((1r,4r)-4-( 6-(phenylsulfonyl)-2-(1H-pyrazol-4-yl)imidazo[4,5-d|pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile, prepared in Example 123, Step A, (227 mg, 0.467 mmol) as a solid followed by DMF (1 mL), CS ² CO ³ (457 mg, 1.40 mmol) and isobutylene oxide (0.13 mL, 1.5 mmol ).The vial was sealed and the contents heated at 110 °C for 30 minutes using a microwave reactor.The reaction was poured into 30 mL of water with vigorous stirring causing a precipitate to form.The solution was stirred for 30 minutes and then the solids were collected by filtration.The solids were air dried for 30 min then placed under high vacuum overnight.The solid was purified by flash column chromatography (40 g SiO ² , 0-6% 2N NH3-MeOH/EA) to provide the title compound (99 mg, 38% yield) as an off-white solid. MS (ESI): mass calc. for C ²⁹ H ³¹ N ⁷ O ³ S, 557.2; m/z found, 558.3 [M+H]+.

[0699] Step B: 2-(( 1r,4r)-4- ( 2- ( 1 -(2-Hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)imidazo[4,5-d] pyrrolo[2,3-b]pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. The title compound (52 mg, 68% yield) was prepared using analogous conditions to those described in Example 1, Step B using 2-((1r,4r)-4-(2-(1-(2-Hydroxy -2-methylpropyl)-1H-pyrazol-4-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (99 mg, 0.18 mmol) instead of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-^pyrrolo[2 ,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. The residue was purified by flash column chromatography (24 g SiO ² , 0-10% 2N NH ³ -MeOH/EA over 12 CV) to provide the title compound. MS (ESI): mass calc. for C ²³ H ²⁷ N ⁷ O, 417.2; m/z found, 418.3 [M+H]+. 1H NMR (500 MHz, DMSO-ds): 11.90 (s, 1H), 8.57 (s, 1H), 8.18 (d, J = 0.8 Hz, 1H), 7.88 ( d, J = 0.8 Hz, 1H)), 7.50 (t, J = 3.0 Hz, 1H), 6.76 (dd, J = 3.5, 1.9 Hz, 1H), 4 .79 (s, 1H), 4.69 -4.49 (m, 1H), 4.16 (s, 2H), 2.57 (d, J = 6.2 Hz, 2H), 2.49 - 2.39 (m, 2H), 1.99 (m, J = 12,1,7.5 Hz, 5H), 1.45-1.25 (m, 2H), 1.14 (s, 6H) .

Example 188 Synthesis and characterization:

2-(8-chloro-1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide

[0700]

[0701] To a vial containing 2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide, as prepared in Example 1, (52 mg, 0.13 mmol) was added CH ³ CN (2.0 mL) and NaHCO3 (62 mg, 0.74mmol). 2-Chloro-1,3-bis(methoxycarbonyl)guanidine (54 mg, 0.26 mmol) was added as a solution in CH ³ CN (2.0 mL) slowly over 5 minutes. The reaction mixture was stirred at room temperature under N ² for 25 min, then poured into a vigorously stirred mixture of 0.1 N sodium thiosulfate (25 mL), saturated aqueous sodium bicarbonate (25 mL) and CH ² Cl ² (50 ml). The organic layer was separated and the aqueous layer was extracted with CH ² CL (2 x 50 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (2-10% MeOH/CH ² CL). The resulting residue was dissolved in N3CH2Cl2 (3 mL), the product precipitated by addition of hexanes (10 mL) and the resulting white solid isolated by filtration to give the title compound (35 mg, 62%). MS (ESI): mass calc. for C22H27ClN6O2, 442.19; m/z found, 443.2 [M+H]+. 1H NMR (500 MHz, DMSO-ds): 12.23 (s, 1H), 8.54 (s, 1H), 8.04-7.97 (m, 1H), 7.65 (d, J =2.9 Hz, 1H), 5.69 - 5.58 (m, 1H), 4.50 (s, 1H), 4.05 (s, 2H), 3.10 (d, J=5, 9 Hz, 2H), 2.57 (d, J=6.3 Hz, 2H), 2.20 - 2.09 (m, 2H), 2.06 1.82 (m, 5H), 1.46 -1.32 (m, 2H), 1.10 (s, 6H).

E x a m p le 189 S in te sis an d c a r c t e r iz a tio n :

2-(8-bromo-1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide

[0702]

[0703] To a vial containing 2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pmdm-2-yl )-W-(2-hydroxy-2-methylpropyl)acetamide, as prepared in Example 1, (52 mg, 0.13 mmol) was added THF (20 mL) followed by N-bromosuccinimide (246 mg, 1, 48 mmol) in a single portion.The reaction mixture was stirred under N ² at room temperature for 5 min, then poured into a vigorously stirred mixture of 0.1N sodium thiosulfate (25 mL), sodium bicarbonate saturated aqueous sodium (25 mL) and CH ² Cl ² (100 mL).The organic layer was separated and the aqueous layer was extracted again with CH ² Cl ² (100 mL).The combined organic layers were dried (MgSO4) and concentrated The residue was purified (FCC, 2-10% MeOH/CH ² Cl ² ) and the fractions containing the product were combined and concentrated The residue was dissolved in N 3 CH 2 Cl 2 (3 mL), the product precipitated by adding of hexanes (10 mL), and the resulting white solid was isolated by filtration to p Provide the title compound (34.5 mg, 9%). MS (ESI): mass calc. for C ²² H ² /BrN ⁶ O ² , 486.14; m/z found, 487.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.33 (s, 1H), 8.53 (s, 1H), 8.05-8.00 (m, 1H), 7.69 (d, J =2.7 Hz, 1H), 5.90 - 5.82 (m, 1H), 4.52 (s, 1H), 4.05 (s, 2H), 3.10 (d, J=5, 9 Hz, 2H), 2.57 (d, J=6.3 Hz, 2H), 2.21-2.11 (m, 2H), 2.03-1.87 (m, 5H), 1, 54-1.43 (m, 2H), 1.10 (s, 6H).

Reference Example 190 Synthesis and Characterization:

2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-8-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide

[0704]

[0705] To a microwaveable vial containing 2-(8-bromo-1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2, 3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide, as prepared in Example 190, (52 mg, 0.13 mmol) was added (2-dicyclohexylphosphino-2' Palladium(II) ,4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate (5.6 mg, 0.0066 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (3.1 mg, 0.0066 mmol). The vial was evacuated, treated with THF (4.0 mL) via syringe, and then vented under N2. Dimethyl zinc (68 mL, 0.66 mmol) was added via syringe, then the reaction mixture was heated to 75 °C for 30 min, then 85 °C for a further 30 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and then extracted with CH ² Cl ² (3 x 50 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified (FCC 6-10% MeOH/CH ² Cl ² ) to provide the title compound as a white solid. (29.5mg, 53%). MS (ESI): mass calc. for C ²³ H ³⁰ N ⁶ O ² , 422.24; m/z found, 423.2 [M+H]+. 1H NMR (600 MHz, DMSO-dsj: 511.51 (d, J=2.7 Hz, 1H), 8.43 (s, 1H), 8.00 (t, J=5.9 Hz, 1H) , 7.27 - 7.19 (m, 1H), 5.09 -4.98 (m, 1H), 4.52 (s, 1H), 4.03 (s, 2H), 3.10 (d , J=5.9 Hz, 2H), 2.60-2.55 (m, 5H), 2.21-2.10 (m, 2H), 2.05-1.85 (m, 5H), 1.40-1.29 (m, 2H), 1.09 (s, 6H).

Re fere n ce e xample 191 S in te sis an d c a c ter iz a tio n:

2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-7-methyl-1,6-dihydroimidazo[4,5-a(]pyrrolo[2,3-b]pyridin-2-yl)-W -(2-hydroxy-2-methylpropyl)acetamide

[0706]

[0707] Step A: 4-chloro-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine. To a 250 mL round bottom flask, NaH (60% dispersion in mineral oil, 1.39 g, 34.8 mmol) was added as a solid. The flask was evacuated and refilled with N ² . DMF (25 mL) was added and the round bottom flask was placed in an ice/water bath and cooled to 3 °C. Next, a solution of 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine (4.07 g, 24.4 mmol) in DMF (34 mL) was added slowly (over 45 min). ). addition funnel and shaken for 45 min. p-Toluenesulfonyl chloride (5.75 g, 29.9 mmol) was dissolved in DMF (33 mL) and the resulting solution added dropwise over 20 minutes. The progress of the reaction was monitored by LCMS analysis. NOTE: Attempts to add additional amounts of TsCl did not further boost the conversion of the reaction. The reaction was slowly poured into 500 mL of ice-water while stirring vigorously, causing a precipitate to form. Then 1M NaOH (35ml) was added and the reaction stirred for 1h. The solids were collected by suction filtration. The solids were ground to a fine powder and dried under vacuum for 1 day using high vacuum (100 mTorr) to provide the title compound (7.82 g, 95%) as a tan powder. MS (ESI): mass calc. for C ¹⁵ H ¹³ ClN ² O ² S, 320.0; m/z found, 321.0 [M+H]+.

1H NMR (500 MHz, CDCls): 58.25 (d, J = 5.3 Hz, 1H), 8.06-7.96 (m, 2H), 7.30-7.23 (m, 2H) , 7.13 (d, J = 5.3 Hz), 1H), 6.42 -6.37 (m, 1H), 2.74 (s, 3H), 2.36 (s, 3H).

[0708] Step B: 4-chloro-2-methyl-5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine. To a solution of 4-chloro-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine ( 3.2 g, 10 mmol) in dry CH ² Cl ² (300 mL) was added n -Bu 4 NNO ³ (4.556 g, 14.96 mmo01)) slowly at -10 °C. Trifluoroacetic anhydride (2.812 mL, 19.95 mmol) was added dropwise over 10 minutes. The reaction was stirred at room temperature for 16h then diluted with CH ² Cl ² , washed with saturated aqueous sodium bicarbonate (100ml X 2) and brine (100ml). The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to provide the title compound (3.1 g, 85% yield). MS (ESI): mass calc. for C15H12ClN3O4S, 365.80; m/z found, 366.0 [M+H]+.

[0709] Step C: 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-7-methyl-6-tosyl-1,6-dihydroimidazo[4,5-a]pyrrolo[2, 3-b]pyridin-2-yl)ethyl acetate. A solution of 4-chloro-2-methyl-5-nitro-1 -tosyl-1 H-pyrrolo[2,3-b]pyridine (818 mg, 2.24 mmol) and 2-((7r,4r )-4-aminocyclohexyl)acetonitrile (intermediate 1, step D, 437 mg, 2.50 mmol) and DIPEA (5 mmol) in DMSO (3 mL) was stirred at 100 °C for 1 h. The reaction was cooled to room temperature and water (100ml) was added. A precipitate formed which was filtered off, dissolved in CH ² Cl ² (50 ml), the organic extracts washed with water (50 ml) and concentrated to dryness. To the residue was added ethyl 3-ethoxy-3-iminopropanoate (1.313 g, 6.711 mmol), sodium dithionate (1.168 g, 6.711 mmol) and DMSO (5 mL) and heated at 100 °C for 3 hours. Water (20 ml) was added and the precipitate that formed was collected by filtration. The precipitate was washed with MeOH and the organic extracts concentrated to dryness to give the crude title compound (1.0 g). MS (ESI): mass calc. for C ²⁸ H ³¹ N ⁵ O ⁴ S, 533.2; m/z found, 534.3 [M+H]+.

[0710] Step D: 2-(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-7-methyl-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b] pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. The title compound was prepared using analogous conditions to those described in Example 30, Step B, and using 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-7-methyl-6-tosyl- Ethyl 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate instead of ethyl 2-(1-((7r,4r)-4-(cyanomethyl) cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3-b]pyridin-2-yl)acetate in step D (10 mg, 11% yield), with purification by flash column chromatography (10% MeOH in CH ² Cl ² ) MS (ESI): mass calc. for C23H30N6O2, 422.2; m/z found, 423.3 [M+H]+.

1H NMR (500 MHz, CDCla): 510.50 (s, 1H), 8.67-8.30 (m, 1H), 7.72 (s, 1H), 7.31-7.06 (br, 1H), 6.34 -6.16 (m, 1H), 4.81 -4.47 (br, 1H), 3.93 (s, 2H), 3.23 (d, J = 6.2 Hz , 2H), 2.59-2.27 (m, 7H), 2.20-1.91 (m, 5H), 1.53-1.05 (m, 8H).

Reference Example 192 Synthesis and Characterization:

2-((7r,4r)-4-(2-(2,5,8,11-Tetraoxatr¡decan-13-¡l)¡m¡midazo[4,5-d]p¡rrolo[2,3 -b]p¡r¡d¡n-1 (6H)-yl)cyclohexyl)acetonitrile

[0711]

[0712] Step A: 2-((ir,4r1-4-(6-(phenylsulfonyl)-2-(2,5,8,11-tetraoxatridecan-13-yl)imidazo[4,5-a(|pyrrolo [2,3-b]pyridine 1(6H)-yl)cyclohexyl)acetonitrile A solution of 2-((7r,4r)-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2 ,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1.97 mg, 0.22 mmol), 2,5,8,11-tetraoxatetradecan-14-al (79 mg, 0.36 mmol ) and sodium hydrosulfite (108 mg, 0.527 mmol) in DMSO (1 mL), MeOH (1 mL), and distilled water (0.5 mL) was heated in a sealed tube at 100 °C for 17 h. filtered through a syringe filter and the filtrate was purified by reverse phase HPLC to provide the title compound (95 mg, 59% yield) as an oil MS (ESI): mass calcd for C ³¹ H ³⁹ N ⁵ O ⁶ S, 609.3, m/z found, 610.2 [M+H]+.

[0713] Step B: 2-((ír,4r)-4-(2-(2,5,8,11-Tetraoxatridecan-13-yl)imidazo[4,5-a|pyrrolo[2,3-b ]pyridin-1( 6H) -yl)cyclohexyl)acetonitrile. The title compound was prepared using analogous conditions to those described in Example 1, Step B (39 mg, 63% yield). The compound was purified by flash column chromatography (16 g silica gel column, 2-10% MeOH in D ^cM ). MS (ESl): mass calc. for C ²⁵ H ³⁵ N ⁵ O ⁴ , 469.3; m/z found, 470.2 [M+H]+. 1H NMR (400 MHz, CDCla) = 10.47 (br s, 1H), 8.76 (s, 1H), 7.41 (br s, 1H), 6.71 (br s, 1H), 4 .54 (br s, 1H), 3.99 (open, 2H), 3.68 - 3.55 (m, 10H), 3.55 - 3.46 (m, 2H), 3.35 (s, 3H), 3.33 - 3.25 (m, 2H), 2.56 (open, 2H), 2.44 (d, J = 6.4 Hz, 2H), 2.18 (d, J = 13 .0 Hz, 2H), 2.13-1.99 (m, 3H), 1.57-1.40 (m, 2H).

Reference Example 193 Synthesis and Characterization:

N-(2-(2-(2-Aminoethoxy)ethoxy)ethyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d] pyrrolo[2,3-b]pyridin-2-yl)acetamide

[0714]

[0715] To a solution of sodium 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)acetate (intermediate 4, 130 mg, 0.360 mmol) and 2,2'-(ethane-1,2-diylbis(oxy))diethanamine (17 mg, 0.11 mmol) in d Mf (1 mL) PyBOP (288 mg, 0.550 mmol) and DIPEA (0.12 mL, 0.72 mmol) were added and stirred at room temperature for 42 h. After removing the DMF in vacuo, the residue was purified by reverse phase HPLC (10-90% CH ³ CN in H ² O, 0.1% TFA) to provide the title compound. This material was dissolved in n-BuOH and saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with n-BuOH (x 3). The organic extracts were dried over Na ² SO ⁴ , filtered and concentrated. The residue was dissolved in 10% MeOH in CH ² Cl ² and the solution filtered through a syringe filter. The filtrate was concentrated to provide the title compound (12 mg, 7%). MS (ESl): mass calc. for C ²⁴ H ³³ N ⁷ O ³ , 467.3; m/z found, 468.1 [M+H]+. 1H NMR (400 MHz, CD ³ OD) = 8.53 (s, 1H), 7.52-7.44 (m, 1H), 6.85 (d, J =3.5 Hz, 1H), 4.63 -4.44 (m, 1H), 4.14 -4.04 (m, 1H), 3.68 - 3.47 (m, 9H), 3.44 (t, J =5.3 Hz, 2H), 2.78 (br s, 1H), 2.63-2.44 (m, 4H), 2.19-1.99 (m, 6H), 1.57-1.43 (m , 2H).

Reference Example 194 Synthesis and Characterization:

2-((1r,4r)-4-(2-((2-(2-methoxyethoxy)ethoxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)- yl)cyclohexyl)acetonitrile

[0716 ]

[0717] Step A: 2-((ir,4r,)-4-(2-((2-(2-methoxyethoxy)ethoxy)methyl)-6-(phenylsulfonyl)imidazo[4,5-a(|pyrrolo [2,3-b]pyridin-1 ( 6H)- yl)cyclohexyl)acetonitrile 2-((1r,4r)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2, 3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 100 mg, 0.228 mmol) was dissolved in DMSO (1.9 mL) and MeOH (0.4 mL) in a 10-microwave vial 2-(2-(2-methoxyethoxy)ethoxy)acetaldehyde (197 mg, 1.22 mmol) was added followed by sodium hydrosulfite (116 mg, 0.57 mmol) The vial was capped and heated to 100 °C for 18 hours.After cooling to room temperature, the mixture was diluted with water (5 mL) and ethyl acetate (5 mL) and then stirred for 5 minutes.The aqueous layer was then extracted with EtOAc ( 3 x 25 mL).The combined organic extracts were dried over sodium sulfate, filtered, and then concentrated to dryness to provide a yellow solid which was used without further purification.MS (ESI): mass calcd for C ²⁸ H ³³ N ⁵ O ⁵ S, 55 1.2; m/z found, 552.3 [M+H]+.

[0718] Step B: 2-((1r,4r)-4-(2-((2-(2-methoxyethoxy)ethoxy)methyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1(6H)-yl)cyclohexyl)acetonitrile. The title compound was prepared using analogous conditions to those described in Example 1, Step B (18.2 mg, 19% yield). The crude material was initially triturated with heptane/DCM and then purified by HPLC using a Phenomonex Gemini 150 mm x 30 mm, 5 gm column using a gradient of 5 to 95% MeCN in water (both phases contained 0.1% MeCN). of TFA) to provide the title compound. MS (ESI): mass calc. for C ²² H ²⁹ N ⁵ O ³ , 411.2; m/z found, 412.2 [M+H]+. 1H NMR (400 MHz, CDCla): 11.78 (s, 1H), 8.83 (s, 1H), 7.54-7.41 (m, 1H), 6.78-6.69 (m , 1H), 4.94 (s, 2H), 4.79 -4.66 (m, 1H), 3.71 - 3.67 (m, 2H), 3.67 - 3.64 (m, 2H) ), 3.64 - 3.60 (m, 2H), 3.54 - 3.51 (m, 2H), 3.36 (s, 3H), 2.65 - 2.48 (m, 2H), 2.43 (d, J=6.3 Hz, 2H), 2.24-2.04 (m, 5H), 1.56-1.42 (m, 2H).

Reference Example 195 Synthesis and Characterization:

2-((1S,4r)-4-(2-(2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile

[0719]

[0720] /V,W-Diisopropylethylamine (144 mg, 1.11 mmol) was added at 0 °C to a solution consisting of 2- ( 1- (( 1r,4r)-4- (cyanomethyl)cyclohexyl)- Sodium 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 4, 200 mg, 0.557 mmol), (S)-pyrrolidin-2-ylmethanol ( 56.3 mg, 0.557 mmol) and dimethylformamide (5 mL). After stirring at 0 °C for 1 hour, PyBOP (311 mg, 0.668 mmol) was added. The mixture was stirred for 4 hours with gradual warming to room temperature before quenching with H ² O (10 mL) and concentrating to dryness. The residue was purified by preparative HPLC using a 150 X 25 mm, X 5 gm DuraShell column (eluent: 18% to 48% (v/v) CH ³ CN and H ² O with 0.05% NH ³ ), and lyophilized to dryness to give the impure product, which was further purified by preparative TLC (eluent: methylene chloride: MeOH = 10:1) to give the title compound (5 mg, 2%) as a white solid. LCMS (ESI): RT = 3.56 min, mass calculated. for C ²³ H ²⁸ N ⁶ O ² , 420.23 m/z; m/z found found, 421.2 [M+H]+. Analytical reverse phase LC-MS was performed using a X-Bridge Shield RP18 column, 50 X 2.1 mm X 5 gm at a flow rate of 0.8 mL/min, eluting with a 0% gradient. to 95% acetonitrile (solvent B) and water with 0.05% NH ³ (aq) (solvent A). The eluent composition was held at 100% A for 1 minute, followed by increasing to 60% B over the course of 4 minutes. The eluent increased to 95% B over the course of for 2 minutes before returning to 100% A within 2 minutes. Total running time was 9.5 minutes. MS (ESI): mass calc. for C ²³ H ²⁸ N ⁶ O ² , 420.2; m/z found, 421.2 [M+H]+. 1H NMR (400 MHz, DMSO-afe) 5 11.84 (br s, 1H), 8.49 (s, 1H), 7.49 - 7.43 (m, 1H), 6.74 -6.68 (m, 1H), 5.17 - 5.12 (m, 0.3H), 4.82 -4.76 (m, 0.7H), 4.49 -4.28 (m, 1H ), 4.27 - 4.20 (m, 0.3H), 4.00 - 3.91 (m, 0.7H), 3.68 - 3.58 (m, 2H), 3.33 - 3.31 (m, 2H), 2.60 - 2.57 (m, 2H), 2.42 - 2.26 (m, 2H), 2.10-1.79 (m, 11H), 1 .43-1.27 (m, 2H).

Reference Example 196 Synthesis and Characterization:

(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl (3S,5S, 7S)-adamantan-1-ylcarbamate

[0721]

[0722] Step A: ^6- dihydroimidazo[4,5-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,(3S,5S,7S)-adamantan-1-ylcarbamate -d]pyrrolo[2,3-b]pyridin-2-yl)methyl A mixture of 2-((7r,4r)-4-(2-(hydroxymethyl)-6-(phenylsulfonyl)imidazo[4,5 -d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (intermediate 7, 35 mg, 0.078 mmol), (3S,5S,7S)-1-isocyanatoadamantane (25 mg, 0 0.14 mmol) and Et3N (0.030 mL, 0.22 mmol) in THF (1.5 mL) and ^{dM f} (0.5 mL) was heated at ⁸⁰ °C for 5 h.More (3S,5S) were added ,7S)-1-isocyanatoadamantane (15 mg, 0.085 mmol) and Et3N (0.030 mL, 0.22 mmol) and the mixture was heated at 90 °C for 17 h After concentration in vacuo, the residue was purified by chromatography flash (20-80% EtOAc in heptane) to provide the title compound (44 mg, 90%) as a white solid MS (ESI): mass calcd for C ³⁴ H ³⁸ N ⁶ O ⁴ S, 626, 3, m/z found, 627.3 [M+H]+.

[0723] Step B: (1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) Methyl (3s,5s,7s)-adamantan-1-ylcarbamate. The title compound (25 mg, 73%) was prepared using conditions analogous to those found in Example 152, step D. The compound was purified by reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 X 30 mm column ( eluent: 10-90% CH ³ CN in H ² O, 0.1% TFA). The concentrated fractions were dissolved in DCM and aqueous NaHCO3 solution. The aqueous portion was separated and extracted with DCM (x3) and EtOAc (x2). The combined organic extracts were dried, filtered, concentrated and further purified by flash column chromatography (2-5% MeOH in DCM). MS (ESI): mass calc. for C ²⁸ H ³⁴ N ⁶ O ² , 486.3; m/z found, 487.4 [M+H]+. 1H NMR (400 MHz, CDCh) 5 = 10.97 (br s, 1H), 8.82 (s, 1H), 7.44 (br s, 1H), 6.72 (br s, 1H), 5 .43 (s, 2H), 4.84 (br s, 1H), 4.59 (br s, 1H), 2.67 - 2.45 (m, 1H), 2.43 (d, J = ^{6 , 6} Hz, 2H), 2.27 - 2.14 (m, 2H), 2.15 - 2.00 (m, 3H), 1.95 (open, ⁶ H), 1.68 (open, ⁶ H), 1.60-1.41 (m, 2H), 1.35-1.19 (m, 2H), 0.92-0.84 (m, 2H).

Reference Example 197 Synthesis and Characterization:

2-(( 1r,4r)-4-(2-(2-(4-methoxypiperidin-1 -yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-¿>]pyridin- 1( ^6H )-yl)cyclohexyl)acetonitrile and its trifluoroacetic acid salt

[0724]

[0725] Step A: 2-((7r,4r)-4-(2-(2-(4-Methoxypiperidin-1-yl)-2-oxoethyl)-6-(phenylsulfonyl)imidazo[4,5-d ]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile.TFA. A solution of 2-(1-((7r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)ethyl acetate (intermediate 3, 55 mg, 0.11 mmol, 4-methoxypiperidine (355 mg, 3.08 mmol) and NH ⁴ NO ³ (20 mg, 0.25 mmol) under Ar was heated at 65 °C for 88 h After concentration, the residue was purified by reverse phase HPLC (10 - 100% CH ³ CN in H ² O, 0.1% TFA) to give the title compound (50 mg, 67%) MS (ESI): mass calculated for C ³⁰ H ³⁴ N ⁶ O ⁴ S, 574.2, m/z found, 575.3 [M+H]+.

[0726] Step B: 2-(( 1r,4r)-4-(2-(2-(4-Methoxypiperidin-1 -yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile as its trifluoroacetic acid salt A solution of 2-((1r,4r)-4-(2-(2-(4-methoxypiperidin-1-yl) -2-oxoethyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile (50 mg, 0.087 mmol) in THF (1 mL) and MeOH (1 mL) was treated with 3 ⁿ NaOH (0.087 mL, 0.26 mmol) for 16 h at room temperature. After concentration in vacuo, the free base, 2-((1r,4r)-4-(2-(2-(4-methoxypiperidin-1-yl)-2-oxoethyl)imidazo4,5-d]pyrrolo[ 2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile was purified by reverse phase HPLC (10 - 90% CH ³ CN in H ² O, 0.1% T ^f A) to give the compound of the title as the salt of trifluoroacetic acid (24 mg, 50%). MS (ESI): mass calc. for C ²⁴ H ³⁰ N ⁶ O ² , 434.2; m/z found, 435.3 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 5 = 8.81 (s, 1H), 7.76-7.72 (m, 1H), 7.09 (br s, 1H), 4.74-4, 49 (m, 1H), 3.95 - 3.83 (m, 2H), 3.60 - 3.48 (m, 2H), 3.47 - 3.37 (M, 1H), 3.40 ( s, 3H), 2.56 (d, J =5.6 Hz, 2H), 2.25-2.07 (m, 5H), 2.08-1.99 (m, 2H), 1.96 -1.85 (m, 2H), 1.85-1.66 (m, 2H), 1.63-1.45 (m, 4H).

Example 198 Synthesis and characterization:

2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-methylacetamide as its trifluoroacetic acid salt

[0727]

[0728] Step A: 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo trifluoroacetic acid salt [2,3-b]pyridin-2-yl)-N-methylacetamide. A solution of 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine -2-yl)ethyl acetate (intermediate 3, 70 mg, 0.14 mmol), 40% methylamine in water (0.30 mL, 3.1 mmol), and EtOH (1 mL) under Ar was heated at 65 °C for 15 min and then stirred at room temperature for 62 h. A few drops of TFA were added and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (10-100% CH ³ CN in H ² O, 0.1% TFA) to give the title compound (63 mg, 75%). MS (ESI): mass calc. for C ²⁵ H ²⁶ N ⁶ O ³ S, 490.2; m/z found, 491.2 [M+H]+.

[0729] Step B: 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b) trifluoroacetic acid salt ]pyridin-2-yl)-N-methylacetamide. The title compound (15 mg, 31%) was prepared using conditions analogous to those found in Example 198, step B, where the free base compound, 2-(1 -((1r,4r)- 4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-methylacetamide was prepared and then purified with reverse phase HPLC using a Varian Pursuit XRs5 Diphenyl 100 X 30 mm column (eluent: 10-90% CH ³ CN in H ² O, 0.1% TFA) was isolated as its trifluoroacetic acid salt. MS (ESI): mass calc. for C ¹⁹ H ²² N ⁶ O, 350.2; m/z found, 351.1 [M+H]+. 1H NMR (400 MHz, CD ³ OD) = 8.80 (s, 1H), 7.75 (d, J =3.0 Hz, 1H), 7.09 (d, J =3.0 Hz, 1H), 4.71 (br s, 1H), 2.99 (s, 1H), 2.86 (s, 1H), 2.82 (s, 3H), 2.56 (d, J =6, 1 Hz, 4H), 2.18-2.07 (m, 5H), 1.61-1.45 (m, 2H).

Reference Example 199 Synthesis and Characterization:

N-((3R,5R,7R)-Adamantan-1-ylmethyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d] pyrrolo[2,3-b]pyridin-2-yl)acetamide as its trifluoroacetic acid salt

[0730]

[0731] The title compound (25 mg, 86%) was prepared using analogous conditions to those found in Example 198 and using (3R,5R,7R)-adamantan-1-ylmethanamine in place of 4-methoxypiperidine in the step A. MS (ESI): calculated mass. for C ²⁹ H ³⁶ N ⁶ O, 484.3; m/z found, 485.4 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 58.79 (s, 1H), 7.73 (d, J =3.5 Hz, 1H), 7.09 (d, J =3.5 Hz, 1H) , 4.66 (br s, 1H), 4.37 -4.32 (m, 1H), 3.00 - 2.93 (m, 2H), 2.56 (d, J =6.1 Hz, 4H), 2.28-2.06 (m, 6H), 2.03-1.92 (m, 3H), 1.77 (d, J = 12.1 Hz, 3H), 1.68 (d , J = 11.6Hz, 3H), 1.61-1.49 (m, 8H).

Example 200 Synthesis and characterization:

2-(1-((7r;4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(4 -cyanophenyl)acetamide

[0732]

[0733] To a solution of 2-(1 -((ir,4r1-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- Sodium il)acetate (50 mg, 0.14 mmol) and 4-aminobenzonitrile (70 mg, 0.59 mmol) in DMF (2 mL) were added HATU (180 mg, 0.47 mmol) and DIPEA (0. 12 mL, 0.72 mmol) and stirred at room temperature for 18 h. After removing the DMF in vacuo, water was added to the residue and the aqueous layer was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered , concentrated and purified by reverse phase HPLC (10 - 90% CH ³ CN in H ² O, 0.1% TFA).The collected TFA salt was neutralized by partitioning between saturated aqueous NaHCO3 and CH ² Cl ² , and Purified again by flash chromatography (4 g column, 0-20% MeOH in CH ² Cl ² saturated with NH ³ ) to give the title compound (10 mg, 16%) as a white solid.MS (ESI ): mass calcd for C ²⁵ H ²³ N ⁷ O, 437.2, m/z found, 438.1 [M+H]+, 1H NMR (400 MHz, CD ³ OD) 58.67 (br s, 1H), 7.80 (d, J =8.1 Hz, 2H), 7.68 (d, J =8.1 Hz, 2H), 7.61 (d, J = 3.5 Hz, 1H), 6.97 (d, J =3.5 Hz, 1H), 4.66 (br s, 1H), 2.61 - 2.47 (m, 4H), 2.23 - 2.08 (m, 5H), 1.58-1.36 (m, 3H), 1.36-1.23 (m, 1H).

Reference Example 201 Synthesis and Characterization:

2-(1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide trifluoroacetic acid

[0734]

[0735] The title compound (40 mg, 83%) was prepared from 2-(1 -((7r,4r)-4-(cyanomethyl)c¡clohex¡lo)-6-(phen¡ lsulfon¡l)-1,6-d¡h¡d¡d¡m¡dazo[4,5-d]pyrro[2,3-b]pyr¡d¡n-2-¡l)ethyl acetate ( Intermediate 3) using analogous conditions to Example 199, using and using 28% NH ⁴ OH in water in place of 40% NH ² Me in water in Example 199, step A. MS (ESI): mass calculated. for C ¹⁸ H ²⁰ N ⁶ O, 336.2; m/z found, 337.2 [M+H]+. 1H NMR (400MHz, CD ³ OD) 58.81 (br s, 1H), 7.75 (d, J =3.5 Hz, 1H), 7.10 (d, J =3.5 Hz, 1H) , 4.69 (br s, 1H), 2.56 (d, J = 6.1 Hz, 4H), 2.27 - 2.09 (m, 6H), 1.66 1.45 (m, 3H ).

Reference Example 202 Synthesis and Characterization:

2-((7r,4r)-4-(2-(tert-butox¡met¡l)¡m¡dazo[4,5-d]p¡rrolo[2,3-b]p¡r¡d¡ n-1(6H)-¡lo)c¡clohex¡l)acetonitr¡le and its trifluoroacetic acid salt

[0736]

[0737] A solution of 2-((7r,4r)-4-(2-(chloromethyl)-6-(phen¡lsulfon¡l)¡m¡midazo[4,5-d]p¡rrolo[ 2,3-b]pyr¡d¡n-1(6H)-¡l)c¡clohexyl)aceton¡trile (intermediate 8.42 mg, 0.090 mmol), 1M KOíBu in THF (0.38 mL, 0.38 mmol) and THF (1.5 mL) was heated at 50 °C for 20 min during which the mixture changed from cloudy to clear and then cloudy again. After concentration, the free base residue, 2-((7r,4r)-4-(2-(tert-butoxy¡methyl)¡m¡dazo[4,5-d]p¡rrolo[2 ,3-b]pyr¡d¡n-1(6H)-yl)cyclohex¡l)aceton¡tr¡lo, was purified by reverse phase HPLC (10 - 90% CH ³ CN in H ² O, 0, 1% TfA) to give the title compound as its trifluoroacetic acid salt (15 mg, 35% yield). MS (ESI): mass calc. for C ²¹ H ²⁷ N ⁵ O, 365.2; m/z found, 366.3 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 58.82 (s, 1H), 7.75 (d, J =3.5 Hz, 1H), 7.08 (d, J =3.5 Hz, 1H) , 5.02 (s, 2H), 4.80 (br s, 1H), 2.58 (d, J = 6.6 Hz, 4H), 2.25 - 2.10 (m, 5H), 1 .63-1.46 (m, 2H), 1.39 (s, 9H).

Reference Example 203 Synthesis and Characterization:

2-((1r,4r)-4-(2-((5-Oxo-3-phenyl-1,2,4-oxadiazol-4(5H)-¡l)methyl)¡m¡dazol [4,5-d]p¡rrolo[2,3-b]p¡r¡d¡n-1 (6H)-¡l)c¡clohexyl)aceton¡tr¡lo

[0738]

[0739] A mixture of the (E)/(Z) isomers of N-((1-((1r,4r)-4-(cyanomethyl)c¡clohex¡l)-1,6-d¡h ¡dro¡m¡dazo[4,5-d]p¡rrolo[2,3-b]p¡rid¡n-2-¡l)met¡l)-N'-h¡drox¡benc¡m¡ Damide (60 mg, 0.13 mmol, prepared in Examples 17A and 17B), CDI (23 mg, 0.14 mmol), and THF (2 mL) were stirred at 70 °C for 1.5 h. LC-MS showed that 20% of the starting material remained and 67% of the desired product was formed. Another portion of CDI (11mg) was added. The mixture was stirred at 70 °C for an additional 1 h. LC-MS showed that 27% of the starting material remained and 50% of the desired product was formed. The reaction mixture was concentrated to dryness under reduced pressure, purified by flash column chromatography (eluent: methylene chloride:methanol = 100:0 to 85:15) and preparative HPLC using a Boston Green ODS 150 X 30 mm X column. 5 gm (eluent: 30 to 40% (v/v) CH3CN and H ² O with 0.1% TFA). The pure fractions were combined and treated with saturated aqueous NaHCO3 until pH = 7-8. The volatile organic solvent was removed under reduced pressure. The precipitate was filtered, washed with water (3ml X 2), lyophilized to dryness to give the title compound (10mg, 17%). Reversed phase LC-MS was performed using a Phenomenex Luna-C ¹⁸ .50 X 2 mm X 5 gm column at a flow rate of 0.8 mL/min, eluting with a 10% to 85% acetonitrile gradient. containing 0.05% TFA (solvent B) and water containing 0.1% TFA (solvent A). The eluent composition was held at 90% A for 0.8 minutes, followed by increasing to 80% B over the course of 3.7 minutes. The eluent was then held at 80% B for 3 minutes before returning to 10% B over the course of 2 minutes. The total execution time was 10 minutes. MS (ESI): mass calc. for C ²⁵ H ²³ N ⁷ O ² , 453.19; m/z found, 454.0 [M+H]+. 1H NMR (400 MHz, DMSO-afe) 11.92 (s, 1H), 8.52 (s, 1H), 7.70 - 7.60 (m, 2H), 7.60 - 7.53 ( m, 1H), 7.53 - 7.38 (m, 3H), 6.71 (s, 1H), 5.41 (s, 2H), 4.61 -4.38 (m, 1H), 2 .64 - 2.56 (m, 2H), 2.37 - 2.16 (m, 2H), 2.08-1.79 (m, 5H), 1.53-1.34 (m, 2H) .

Reference Example 204 Synthesis and Characterization:

N-((1-((7r,4r1-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)-N '-hydroxycyclohexanecarboximidamide

[0740]

[0741] Step A: Cyclohexanecarbaldehyde oxime. A solution consisting of cyclohexanecarbaldehyde (5.00 g, 44.6 mmol), hydroxylamine hydrochloride (9.29 g, 134 mmol), sodium acetate (10.97 g, 133.7 mmol), ethanol (150 mL ) and water (30 mL) was stirred at 70 °C for 10 h. The mixture was concentrated under reduced pressure and the residue was diluted with water (40ml) and extracted with ethyl acetate (80ml X 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to provide the title compound (5.1 g, 90%) as a colorless oil. 1H NMR (400 MHz, CDC ¹³ ) 59.10 (br s, 1H), 7.33 (d, J = 6.0 Hz, 0.6H), 6.54 (d, J = 7.2 Hz, 0.3H), 3.04-2.91 (m, 0.3H), 2.29-2.16 (m, 0.7H), 1.88-1.59 (m, 5H), 1, 42-1.11 (m, 5H).

[0742] Step B: N-hydroxycyclohexanecarbimidoyl chloride. 1-Chloropyrrolidine-2,5-dione (6.30 g, 47.2 mmol) was added to a solution consisting of cyclohexanecarbaldehyde oxime (3.0 g, 24 mmol) and N,N-dimethylformamide (20 mL). and the mixture was stirred for 2h at room temperature under nitrogen. The mixture was diluted with ethyl acetate (200ml) and washed with water (50ml x 3). The organic layer was dried over anhydrous Na ² SO ⁴ , filtered and evaporated to dryness in vacuo to give the crude product, which was purified by flash column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 to 100:20) to give the title compound (2.1 g, 55%) as a colorless oil. 1H NMR (400 MHz, CDC ¹³ ) 58.56-8.35 (m, 1H), 2.52-2.38 (m, 1H), 1.99-1.89 (m, 2H), 1, 86-1.75 (m, 2H), 1.73-1.64 (m, 1H), 1.50-1.38 (m, 2H), 1.35-1.15 (m, 3H).

[0743] Step C: tert-butyl ((1-((7r,4r,M-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)methyl)carbamate A solution consisting of 2-((7r,4rJ-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b] pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 5.0 g, 11 mmol), tert-butyl carbamate (2-oxoethyl) (4.2 g, 26 mmol), sodium hydrosulfite (9, 9 g, 57 mmol), DMSO (25 mL), methanol (75 mL) and water (50 mL) was stirred at 100 °C for 3 h The mixture was diluted with water (50 mL) and extracted with dichloromethane ( 100 mL x 2) The combined organic extracts were dried over Na ² SO ⁴ , filtered, and concentrated under reduced pressure to provide the crude product, which was purified by flash column chromatography (eluent: petroleum ether: ethyl acetate). = 100:0 to 40:60) to give the title compound as a light yellow solid (3.6 g, 52%) LCMS (ESI): RT = 0.75 min, mass calculated for C ²⁸ H ³² N ⁶ O ⁴ S, 548.22; m/z found, 549.1 [M+H]+. Reversed phase LC-MS was carried out using a Merck RP-18e 3 gm 32532 mm column with a flow rate of 1.5 mL/min. The HPLC solvent system was a gradient starting with 95% water containing 0.038% TFA (solvent A) and 5% acetonitrile containing 0.02% TFA (solvent B), followed by a gradient to 5% solvent A and 95% solvent B over the next 0.7 min. This eluent composition was held for 0.4 minutes before returning to 95% solvent A and 5% solvent B over the next 0.4 minutes. Total run time was 1.5 minutes. 1H NMR (400 MHz, CDCh) 58.83 (s, 1H), 8.26 - 8.19 (m, 2H), 7.84 (d, J = 4.0 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.51 - 7.44 (m, 2H), 6.83 (d, J = 4.0 Hz, 1H), 5.41 (br.s, 1H), 4 .67 (d, J = 5.6 Hz, 2H), 4.65 - 4.57 (m, 1H), 2.40 (d, J = 6.4 Hz, 2H), 2.36 - 2, 23 (m, 2H), 2.19-2.11 (m, 2H), 2.03-1.90 (m, 3H), 1.49-1.42 (m, 11H).

[0744] Step D: tert-butyl ((1-((7r,4r,M-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methyl)carbamate An aqueous KOH solution (3.6 mL, 11 mmol) was added to a solution consisting of tert-butyl ((1-((7r,4rM-(cyanomethyl)cyclohexyl)-6- (phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate (2.0 g, 3.6 mmol) and 1,4-dioxane (20 mL).The resulting mixture was stirred at 80 °C for 2 h.After cooling to room temperature, the reaction mixture was adjusted to pH = 7-8 with 1N HCl.The volatiles were removed under reduced pressure, diluted with water (20ml) and extracted with ethyl acetate (50ml X 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound as a brown solid (crude, ^1.6 g), which was used in the next step without purification. LCMS (ESI): RT = 0.63 min, mass calculated. for C ²² H ²⁸ N ⁶ O ² , 408.23; m/z, found 409.0 [M+H]+. Reverse phase LC-MS was carried out using a Merck RP-18e 3 gm X 25 X 2 mm column with a flow rate of 1.5 mL/min. The HPLC solvent system was a gradient starting with 95% water containing 0.038% TFA (solvent A) and 5% acetonitrile containing 0.02% TFA (solvent B), followed by a gradient to 5% solvent A and 95% solvent B over the next 0.7 min. This eluent composition was held for 0.4 minutes before returning to 95% solvent A and 5% solvent B over the next 0.4 minutes. Total run time was 1.5 minutes. 1H NMR (400 MHz, DMSO-dsj 511.87 (s, 1H), 8.52 (s, 1H), 7.56-7.49 (m, 1H), 7.47 (t, J = 3, 2 Hz, 1H), 6.73 -6.69 (m, 1H), 4.68 -4.58 (m, 1H), 4.54 (d, J = 5.6 Hz, 2H), 2, 59 (d, J = 6.0 Hz, 2H), 2.42-2.28 (m, 2H), 2.07-1.95 (m, 3H), 1.94-1.84 (m, 2H), 1.46-1.35 (m, 11H).

[0745] Step E: 2-((7r,4rM-(2-(Aminomethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile.HCl A solution of tert-butyl ((1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)carbamate ( ^1.6 g, 3.9 mmol) and methylene chloride (15 mL) was treated with 4 M HCl in 1,4-dioxane (8.0 mL, 32 mmol) at 15 °C for 30 min The reaction mixture was concentrated to dryness under reduced pressure to provide the crude title compound as a brown solid, which was used in the next step without purification (crude, 1.5 g) LCMS (ESI): Rt = 0.16 min, mass calculated for C ¹⁷ H ²⁰ N ⁶ , 308.17, m/z found 308.9 [M+H]+ Reversed phase LC-MS was carried out using a Merck RP column 3 gm x 25 x 2 mm -18e at a flow rate of 1.5 mL/min The HPLC solvent system was a gradient starting with 95% water containing 0.038% TFA (solvent A) and 5% acetonitrile containing 0.02% TFA (solvent B), followed by a gradient to 5% solvent A and 95% solvent B over the next 0.7 min. This eluent composition was held for 0.4 minutes before returning to 95% solvent A and 5% solvent B over the next 0.4 minutes. Total run time was 1.5 minutes. 1H NMR (400 MHz, DMSO-cfe) 512.53 (s, 1H), ^{8 , 8 8} (s, 1H), ^{8 , 8 6} (br. s, 3H), 7.67 (t, J = 3 .2 Hz, 1H), 6.93 (s, 1H), 4.71 -4.63 (m, 2H), 4.60 -4.42 (m, 1H), 2.60 (d, J = 6.0 Hz, 2H), 2.36-2.21 (m, 2H), 2.12-1.93 (m, 5H), 1.56-1.42 (m, 2H).

[0746] Step F: N-((1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 -yl)methyl)-N'-hydroxycyclohexanecarboximidamide. Solution consisting of 2-((7r,4r)-4-(2-(aminomethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl) hydrochloride acetonitrile (Intermediate 5, 150 mg, 0.440 mmol), N-hydroxycyclohexanecarbimidoyl chloride (70.3 mg, 0.440 mmol, Example 205, Step B), triethylamine (132 mg, 1.31 mmol), and N,N- dimethylformamide ( 7.5 ml) was stirred for 2 hours at room temperature. The mixture was filtered and the filtrate was concentrated and purified by preparative HPLC using a Phenomenex Gemini 150 x 25 mm x 10 mm column (eluent: 26% to 56% (v/v) CH ³ CN and H ² O with 0. 05% ^NH3 ). The pure fractions were collected and concentrated to dryness. under reduced pressure to provide the title compound (53 mg, 28%) as a white solid. LCMS (ESI): T ^r = 2.39 min, mass calculated. for C ²⁴ H ³¹ N ⁷ O, 433.26; m/z found 434.1 [M+H]+. Reversed phase LC-MS was performed using a Phenomenex Luna-C ¹⁸ column, 50 x 2 mm x 5 gm with a flow rate of 0.8 mL/min, eluting with a 10% to 80% acetonitrile gradient. containing 0.05% TFA (solvent B) and water containing 0.1% TFA (solvent A). The eluent composition was held at 10% B for 0.8 minutes, followed by an increase to 80% B over the course of 3.7 minutes. The eluent was held at 80% B for 3 minutes before returning to 10% B over the course of 2 minutes. Total running time was 9.5 minutes. MS (ESI): mass calc. for C ²⁴ H ³¹ N ⁷ O, 433.3; m/z found, 434.1 [M+H]+. 1H NMR (400 MHz, DMSO-daj 5 11.91 - 11.83 (m, 1H), 9.16 (s, 1H), 8.57 - 8.50 (m, 1H), ^{7 , 4 9} - ^{7 , 4 4} (m, ^1H ), 6.74 -6.67 (m, 1H), 6.25 -6.17 (m, 1H), 4.74 -4.57 (m, 3H), 2.60 (d, J = 6.0 Hz, 2H), 2.53 - 2.51 (m, 1H), 2.44 - 2.26 (m, 2H), 2.06-1.89 ( m, 5H), 1.68-1.40 (m, 7H), 1.30-1.07 (m, 5H).

Reference Example 205 Synthesis and Characterization:

2-(4-(2-(2-Oxo-2-(piperidin-1-yl)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo [2,2,2]octan-1-yl)acetonitrile

[0747]

[0748] A mixture of 2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yyl)-1,6-dihydroimidazo[4,5-a]pyrrolo[2,3- Sodium b]pyridin-2-yl)acetate (Intermediate 11, 200 mg, 0.518 mmol, crude), piperidine (49 mg, 0.57 mmol), PyBrOP (265 mg, 0.569 mmol), W,W-diisopropylethylamine ( 0.67 mL, 1.6 mmol) and anhydrous DMF (6 mL) was stirred at room temperature for 15 hours and diluted with H ² O (20 mL). The mixture was extracted with ethyl acetate (20 ml X 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (eluent: 25 to 55% (v/v) CH ³ CN and H ² O with 0.05% NH ⁴ HCO ³ ) to give the title compound (57 mg, 26 ) as a white solid. MS (ESI): mass calc. for C ²⁵ H ³⁰ N ⁶ O, 430.3; m/z found, 431.2 [M+H]+. 1H NMR (400 mHz, DMSO-afe) 5 11.88 (br s, 1H), 8.48 (s, 1H), 7.52 (d, J = 3.2 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 4.28 (s, 2H), 3.51 - 3.47 (m, 4H), 2.48 - 2.35 (m, 6H), 1, 82-1.73 (m, 6H), 1.68-1.41 (m, 8H).

Reference Example 206 Synthesis and Characterization:

2-(1-(4-(Cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- il)acetamide

[0749]

[0750] Step A: 2-(1 -(4-(Cyanomethyl)bicyclo[2,2,2]octan-1-yl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d] pyrrolo[2,3-b]pyridin-2-yl)acetamide. A mixture of 2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-2-yl)acetate (intermediate 10, 150 mg, 0.282 mmol), 28% aqueous ammonium hydroxide solution (2 mL), and EtOH (10 mL) in a 50 round bottom flask mL was stirred at room temperature overnight. Additional 28% aqueous ammonium hydroxide solution (18 mL) and THF (5 mL) were added. The mixture was stirred at room temperature for another 24 hours and concentrated to dryness under reduction. The residue was purified by preparative TLC (eluent: CH ² Ch: MeOH = 20:1) to give the title compound (80 mg, 56%) as a white solid. R f (CH ² Cb:MeOH = 20:1), 0.3.

[0751] Step B: 2-(1-(4-(Cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)acetamide,2,2,2-trifluoroacetate. A solution of 2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-2-yl)acetamide (80 mg, 0.16 mmol), 1N NaOH (aq) (0.5 mL, 0.5 mmol), THF (2 mL), and MeOH (2 ml) was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was partitioned between water (5ml) and ethyl acetate (20ml X 2). The combined organic phases were washed with H ² O (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC (eluent: 10% to 30% (v/v) CH ³ CN and H ² O with 0.1% TFA to give the title compound (23 mg, 39%) as a white solid. MS (ESI): mass calc. For C ²⁰ H ²² N ⁶ O, 362.2; m/z found, 363.1 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 58.77 (s, 1H), 7.77 (d, J = 3.2 Hz, 1H), 6.91 (d, J = 3.6 Hz, 1H) , 4.46 -4.44 (m, 2H), 2.69 - 2.65 (m, 6H), 2.51 (s, 2H), 2.03 - 2.00 (m, 6H).

Reference Example 207 Synthesis and Characterization:

2-(1-(4-(Cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)-N-phenylacetamide

[0752]

[0753] The title compound (7 mg, 99%) was prepared using analogous conditions to those found in Example 205 and using 2-(1 -(4-(cyanomethyl)bicyclo[2,2,2]octan-1 sodium -yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 11, 200 mg, 0.52 mmol) and aniline (53 mg , 0.57 mmol) instead of piperidine. MS (ESI): mass calc. For C ²⁶ H ²⁶ N ⁶ O, 438.2; m/z found, 439.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 58.55 (s, 1H), 7.59-7.55 (m, 2H), 7.53 (d, J =3.4 Hz, 1H), 7, 36 - 7.30 (m, 2H), 7.15 - 7.09 (m, 1H), 6.73 (d, J =3.4 Hz, 1H), 3.35 (s, 2H), 2 .70-2.60 (m, 6H), 2.45 (s, 2H), 2.00-1.92 (m, 6H).

Reference Example 208 Synthesis and Characterization:

2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)-N-(cyclohexylmethyl)acetamide

[0754]

[0755] The title compound (70 mg, 29%) was prepared using analogous conditions to those found in Example 205 and using 2-(1 -(4-(cyanomethyl)bicyclo[2,2,2]octan-1 sodium -yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (intermediate 11, 200 mg, 0.52 mmol) and cyclohexylmethanamine (64 mg , 0.57 mmol) instead of piperidine. MS (ESI): mass calc. for C ²⁷ H ³⁴ N ⁶ O, 458.3; m/z found, 459.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 58.53 (s, 1H), 7.51 (d, J = 3.5 Hz, 1H), 6.71 (d, J = 3.5 Hz, 1H) , 4.22 -4.18 (m, 2H), 3.08 (d, J = 6.8 Hz, 2H), 2.63 - 2.56 (m, 6H), 2.46 (s, 2H ), 1.97-1.91 (m, 6H), 1.80-1.73 (m, 4H), 1.72-1.65 (m, 1H), 1.57-1.46 (m , 1H), 1.34-1.17 (m, 3H), 1.03-0.91 (m, 2H).

Reference Example 209 Synthesis and Characterization:

2-(1-(4-(Cyanomethyl)bicyclo[2,2,2]octan-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)-N-methylacetamide

[0756]

[0757] The title compound (24 mg, 12%) was prepared using analogous conditions to those found in Example 205 and using sodium 2-(1-(4-(cyanomethyl)bicyclo[2,2,2]octan- 1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 11,200 mg, 0.52 mmol) and methanamine (0.78 mL, 0.57 mmol) instead of piperidine. MS (ESI): mass calc. for C ²¹ H ²⁴ N ⁶ O, 376.2; m/z found 377.2 [M+H]+. 1H NMR (400 MHz, CD ³ OD) 58.52 (s, 1H), 7.50 (d, J = 3.5 Hz, 1H), 6.71 (d, J = 3.5 Hz, 1H) , 4.19 (s, 2H), 2.77 (s, 3H), 2.62-2.55 (m, 6H), 2.45 (s, 2H), 1.97-1.91 (m , 6H).

Polymorph Screening Example

[0758] Some embodiments of compounds according to this invention as free bases exhibit multiple crystal configurations having complex solid state behavior, some of which in turn may exhibit distinctive characteristics from one another due to different amounts of incorporated solvent. Some embodiments of compounds according to this invention are in the form of pseudopolymorphs, which are embodiments of the same compound that exhibit differences in lattice composition due to different amounts of solvent in the lattice itself. In addition, channel solvation may also be present in some crystalline embodiments of compounds according to this invention, in which the solvent is incorporated into channels or voids that are present in the crystal lattice. For example, the various crystal configurations given in Table 2 were found for compound Ex. 1. Due to these characteristics, non-stoichiometric solvates were often observed, as illustrated in Table 2. Furthermore, the presence of such channels or voids in the crystalline structure of some embodiments according to this invention allow for the presence of water and/or solvent. molecules that are held within the crystal structure with varying degrees of binding strength. Consequently, changes in specific environmental conditions can easily lead to some loss or gain of water molecules and/or solvent molecules in some embodiments according to this invention. It is understood that the "solvation" (third column of Table 2) for each of the embodiments listed in Table 2 is the Solvation Formula, and that the actual determination thereof as a stoichiometric number (fourth column from Table 2) may vary slightly from the Formula solvation depending on actual environmental conditions when determined experimentally. For example, if about half of the water molecules in one embodiment can be present as hydrogen bonds to the active compound in the crystal lattice, while about the other half of the water molecules can be in channels or voids in the crystal lattice then changes in ambient conditions can alter the amount of loose water molecules contained in voids or channels and thus give rise to a slight difference between the Solvation Formula which is assigned according to, for example, single crystal diffraction, and stoichiometry which is determined by, for example, thermogravimetric analysis coupled with mass spectroscopy.

Table 2. Embodiments of crystalline forms of the compound Ex. 1

[0759] The compound which was obtained as described in Example 1 was further crystallized by preparing a suspension in DCM (1:3, eg 10 g of compound in 30 mL of DCM) which was stirred at 40 °C for 4 hours, and stirred further for 14 hours at 25 °C, then slowly added heptane (1:2, e.g., 20 mL heptane in compound/suspension/DCM solution) at 25 °C, stirred at 40 °C for 4 hours, cooled to 25°C and stirred for a further 14 hours at 25°C. Subsequent filtration led to compound Ex. 1 as an off-white solid, which was identified as a monohydrate, an embodiment Is.

[0760] Embodiments 1-10 in Table 2 and Fig. 2 are crystalline. Embodiments 1s and 1a to 1h are isostructural. Embodiment Is crystallizes in a P-1 centrosymmetric triclinic space group. The term "Embodiment 1" refers collectively to Isostructural Embodiments 1s and 1a to 1h. Any of said embodiments 1s and 1a to 1h is sometimes referred to as an isostructural element of embodiment 1 or simply an element of embodiment 1. Embodiments 3b, 3c, 3d and 3e are isostructural and crystallize in the monoclinic system, space group C 2/c. The term "embodiment 3" refers collectively to isostructural embodiments 3b, 3c, 3d and 3e. Any of said embodiments 3b, 3c, 3d and 3e is sometimes referred to as an isostructural element of embodiment 3 or simply an element of embodiment 3. Isostructural embodiments are such that they possess similar crystal structure properties ( same symmetries and similar unit cell). parameters and crystal packing) while having different chemical compositions (i.e., different solvents and/or water molecules incorporated into the crystal lattice). Unit cell parameters in isostructural embodiments may differ slightly due to different composition (solvent or water incorporated into the crystal structure). The embodiments referenced in Table 2 were prepared and/or interconverted as shown schematically in Fig. 2 and as described in more detail in the following selection techniques.

[0761] Screening included crystallization protocols such as solvent equilibration in pure solvents, evaporative crystallization, chilling crystallization with hot filtration, antisolvent shock crystallization, and thermocycling crystallization. The solids were analyzed by HT-XRPD. Where appropriate, the mother liquor was completely evaporated and the remaining solids were also analyzed by HT-XRPD. The predominant solid form that was identified was the starting material embodiment Is as a monohydrate.

Solvent equilibrium at 25 °C and 50 °C

[0762] Long-term suspension experiments were performed by suspending the Compound I embodiment in twenty neat solvents and shaking at room temperature for two weeks and at 50°C for one week. At the end of the equilibration time, the residual solids were separated from the mother liquor. The solids were dried at ambient conditions and dried under vacuum (5 mBar) before being analyzed by HT-XRPD. Subsequently, the solids were exposed to accelerated aging conditions (40°C / 70% relative humidity) for two days and again analyzed by HT-XRPD.

[0763] From most crystallization solvents, the starting material was obtained as Embodiment I. From various crystallization solvents, the patterns of HT-XRPD were found to be similar to those of Embodiment initial Is. Peak shifts and/or additional peaks were identified in most of these diffraction patterns. Each of these patterns corresponded to an embodiment that was labeled as one of 1a to 1H, and based on the similarities in the HT-XRPD diffraction patterns for such embodiments, they are presented as embodiments that are isostructural elements of Embodiment 1. All isostructural elements from Embodiment 1 converted to Embodiment 1 a after exposure at 40°C and 75% RH for two days.

[0764] The embodiment becomes the hydrated embodiment 10 when exposed to 100% RH at 25°C. However, embodiment 10 was not physically stable under ambient conditions. While the embodiment crystallizes in the triclinic system, space group P-1, embodiment 10 was found to crystallize in the monoclinic system, space group C 2/c. Embodiment 10 had limited physical stability at ambient conditions and was converted to another embodiment, such as 1s or 1a. This behavior is attributable to an unevenly strong binding of all the hydration/solvation molecules. In this case, embodiment 10 would have a less tightly bound second water molecule that would be lost at ambient conditions. More precisely, the physical stability of embodiment Is was investigated in climatic chambers by exposing a 20 mg sample of said embodiment to 40 °C and 70% relative humidity for four days, and another 20 mg sample of the same embodiment was also exposed for four days. days at 25°C and 100% relative humidity. After four days, the various solid samples were analyzed by HR-XRPD, the crystal cell parameters determined and the diffractograms indexed. The diffractograms are shown in FIG. 6. From bottom to top, the first diffractogram in FIG. 6 corresponds to embodiment Is as starting material, and the second corresponds to the same form after 4 days exposure at 40°C and 70% relative. humidity, indicated as "Is 70 RH" in the same figure. This analysis revealed that the initial embodiment Is had been recovered albeit with a small amount of a second crystalline form which was possibly another hydrated embodiment with higher water content. The indexing of such a form was not possible due to the small number in which it was present. The third diffractogram corresponds to embodiment Is after a 4-day exposure to 25°C and 100% relative humidity, indicated as "10" in the same figure. These conditions lead to the conversion of embodiment Is to embodiment 10, with little contamination of the initial embodiment Is and solvation as characterized in Table 2. Upon dehydration, both embodiments Is and 10 recrystallized in the anhydrous form with a melting point of 148°. c.

[0765] Solvent equilibration at room temperature produced embodiment 1b with toluene as crystallization solvent, and embodiment If with p-xylene as crystallization solvent.

[0766] Three additional solid embodiments were identified and designated as embodiments 2, 3, and 7. Embodiment 2 was identified from the solvent equilibration experiment performed at room temperature in 1,4-dioxane, while Embodiment 7 was found to be a mixture with Embodiment I is in the single solvent equilibrium experiment at 50 °C from heptane. Several similar but not identical diffractograms were identified and grouped as Embodiment 3b, 3c, 3d and 3e which are isostructural elements of Embodiment 3. The isostructural elements of Embodiment 3 are were found mixed with elements of embodiment 1. Mixtures containing elements of embodiment 3 were transformed in some cases to embodiment 1a or mixtures of embodiments 1a and 3e. Embodiment 7 appeared to be physically stable, but Embodiment 2 converted to Embodiment 3e after exposure to AAC for two days.

evaporative crystallization

[0767] The saved mother liquor from solvent equilibration experiments performed at room temperature were used for slow evaporative crystallization experiments. The mother liquor was filtered to remove any particulate matter and allowed to slowly evaporate at ambient conditions. The obtained solids were analyzed by HT-XRPD and again after exposure to AAC for two days.

[0768] Due to poor solubility of compound Ex. 1 in some of the solvents, no solids were recovered when said solvents were used. In experiments where solids had precipitated, an amorphous residue or isostructural elements of Embodiment 1 or 3 were recovered. During the stability study, the different elements of Embodiment 1 were converted to Embodiment 1a while the sample of embodiment 3 appeared to be physically stable. The amorphous solids in some cases remained amorphous after the stability study, became deliquescent, or showed some signs of crystallinity.

cooling crystallization

[0769] The mother liquors from the solvent equilibration experiments performed at 50°C were filtered at 50°C to remove any particulate matter. Suspensions at 50°C were filtered using 0.2 qm PTFE filters, and solutions were placed at 5°C and aged for 72 hours. When solids had precipitated during aging, these solids were separated from the liquid, dried at ambient conditions and in vacuo, and analyzed by HT-XRPD. The remaining mother liquor was allowed to slowly evaporate and the remaining solids were analyzed by HT-XRPD. Samples in which no precipitation occurred were placed under vacuum and the dry solids were analyzed by HT-XRPD. All solids were then exposed to AAC (2 days at 40 °C/70% RH) and reanalyzed by HT-XRPD.

[0770] Solids did not precipitate on cooling some of the solutions, in which case the solutions evaporated at ambient conditions. Due to the low solubility of compound Ex. 1 in some solvents, no solids were obtained from some solutions.

[0771] From four solvents (2-propanol, 2-butanone, acetonitrile and methanol), precipitation occurred. Embodiment 6 was identified after evaporation of a single mL scale chill crystallization experiment in 800 |uL acetonitrile, 25 mg/mL concentration. Embodiment 6 appeared to be a stable solid form after 2 days of AAC and appeared to be an unsolved embodiment.

Evaporative cooling/crystallization to scale |uL

[0772] mL-scale evaporative cooling/crystallization experiments were performed in a 96-well plate, using 12 neat solvents and 12 solvent mixtures and applying four temperature profiles. Approximately 4 mg of Embodiment Is were dispensed solids into each well. Subsequently, the crystallization solvents (80 ql) and solvent mixtures were added to reach a concentration of 50 mg/ml, and the plate, with each well individually sealed, to subsequently undergo one of four temperature profiles. Once the temperature profile was completed, the solvents were allowed to evaporate at low ambient pressure (24 hours) and the remaining solids were analyzed by HT-XRPD before and after exposure to AAC for 2 days (40 °C/70 % RH).

[0773] Elements of embodiments 1 and 3 were found in most solvent systems and temperature profiles. However, some trend of solid form versus temperature profile was observed. Embodiment 1b was mainly identified from the short temperature profiles (3 hour aging). However, the same solvent systems with long aging times led to the identification of Embodiment If, elements of Embodiment 3, or mixtures of elements of Embodiment 1 and 3. Embodiment 3c is obtained with 1,4-dioxane as crystallization solvent and a temperature profile of 50°C as initial temperature, maintained for 60 min, followed by cooling at a rate of 1°C/h until a final temperature of 20°C, maintained for 48 hours; Embodiment 3d was obtained with tetrahydrofuran as crystallization solvent and the same temperature profile as for Embodiment 3c.

[0774] Embodiment 4 was identified in experiments performed in methanol/water (50/50, v/v), THF and DCM/IPA (50/50, v/v) when short aging conditions were applied. Embodiment 4 was obtained by treating Embodiment I with a mixture (50/50) of water and methanol and a temperature profile of 50 °C as the starting temperature, held for 60 min, followed by cooling at a rate of 20 °C/h for a final temperature of 5 °C, held for 3 h, which produced Embodiment 4 together with Embodiment 1 b. Embodiment 4 together with Embodiment 1b was also obtained by treating Is with a mixture (50/50) of water and methanol and a profile temperature of 50 °C as initial temperature, maintained for 60 min, followed by cooling at a rate of 20 °C. C/h until a final temperature of 20°C, maintained for 3 h. Embodiment 4 did not appear to be physically stable under ambient conditions. Cooling crystallization experiments resulted in embodiment 1c from ethyl acetate/1,4-dioxane (50/50, v/v) as crystallization solvent and a temperature profile of 50 °C as temperature. initial, maintained for 60 min, followed by cooling at a rate of 1°C/h to a final temperature of 5°C, maintained for 48 h; run 1d from acetonitrile/chloroform (50/50, v/v) as crystallization solvent and a temperature profile of 50 °C as starting temperature, held for 60 min, followed by cooling at a rate of 1 °C/ h for a final temperature of 5°C, maintained for 48 h; and embodiment 1e of ethyl acetate/1,4-dioxane (50/50, v/v) as crystallization solvent and a temperature profile of 50 °C as starting temperature, held for 60 min, followed by cooling at a rate of 1 °C/h up to a final temperature of 20 °C, maintained for 48 h.

[0775] Embodiment 5 was identified in experiments performed in chloroform as the crystallization solvent and a temperature profile of 50 °C as the starting temperature, held for 60 min, followed by cooling at a rate of 1 °C/h until a final temperature of 20°C, maintained for 48 h.

[0776] Similar conversions were observed during the stability study as previously observed in the other crystallization methods. In most cases, all solid forms were converted to Embodiment 1a or mixtures containing Embodiment 1a.

Evaporative crystallization from solid mixtures

[0777] In evaporative crystallization using solvent/anti-solvent mixtures, clear solutions of a compound are prepared from which the solvent first evaporates (high vapor pressure), causing the compound to precipitate to some extent in crystal shape. These crystals then act as seeds when the antisolvent evaporates (lower vapor pressure).

[0778] Compound Ex. 1 did not completely dissolve in each of the solvent systems. Therefore, all experiments included filtration prior to evaporation.

[0779] The results of HT-XRPD analysis demonstrated that compound Ex. 1 crystallized mainly as embodiment Is upon evaporation of mixed solvents. This was observed for the following solvent/antisolvent systems: tetrahydrofuran/water, acetonitrile/water, chloroform/ethanol, methanol/ethyl acetate, 2-butanone/isopropanol, and heptane/acetone. From two systems, acetone/cumene and 1,4-dioxane/ethyl formate, isostructural embodiments 3b and 3e were identified, which after AAC became different mixtures of embodiments 1a and 3d, and Is and 3e, respectively.

antisolvent crystallization

[0780] Saturated solutions of compound Ex. 1 were prepared in pure solvents. Antisolvent additions were performed in forward and reverse additions. In the direct addition, the antisolvent was added in three aliquots to the compound solution. The reverse addition was performed by adding one volume of compound solution to a large excess of antisolvent (20 mL).

[0781] After precipitation, the solids were separated from the liquids, dried at ambient conditions and dried under vacuum (5 mbar) before being analyzed by HT-XRPD. Experiments in which no precipitation occurred after antisolvent addition were stored at 5°C for 48 hours to induce precipitation. The precipitated solids were then separated and analyzed by HT-XRPD. When no solids were obtained, the solutions were evaporated under mild conditions and the residual solids were analyzed by HT-XRPD. All solids were exposed to Ac (2 days at 40 °C/70% RH) and reanalyzed by h T-XRPD.

[0782] Direct crystallization of the antisolvent showed precipitation in all cases. All solids could be classified as isostructural elements (Is, 1b, 1j, 1f) of Embodiment 1 or Embodiment 3 (3b, 3d, 3f). After exposure to AAC, all solid samples were converted to embodiment la, except one that was converted to a mixture of embodiments 1a and 3e.

[0783] Reverse antisolvent crystallization experiments performed in DMSO as solvent gave different solid forms depending on the antisolvent used. With dichloromethane or p-xylene, isostructural elements (Is and 1b) of embodiment 1 were identified, while with MTBE an amorphous residue was obtained. Evaporation of two solutions with heptane and water as antisolvents that had not precipitated after the addition of the antisolvent led to an oil. Conversions to embodiment 1a were observed after AAC, and the amorphous residues became deliquescent.

Hot filtration experiments

[0784] Hot filtration cooling crystallization experiments were performed from solutions supersaturated samples of the compound Ex. 1 prepared at 50°C in different mixtures of solvents. Hot filtered solutions were subjected to a 48 hour chill profile. Vials in which solids had precipitated after temperature profiling were centrifuged and solids separated from liquid and analyzed by HT-XRPD (after vacuum drying). If no solids had precipitated, the solutions were evaporated in vacuo and the solids analyzed by HT-XRPD. All solids were exposed to AAC (2 days at 40 °C/70% RH) and reanalyzed by HT-XRPD. In half of the hot filtration experiments no precipitation occurred and after evaporation of the solvents not enough solids were recovered due to poor solubility of compound Ex. 1 in those solvent systems. In three experiments, an amorphous residue was recovered which after AAC crystallized from a mixture of elements of embodiment 1 (Is or la) and 3 (3e) or became deliquescent. Embodiment 5 was identified from the experiment in acetone/chloroform (50/50, v/v). This embodiment appeared to be physically unstable as conversion to embodiment 1a was observed after AAC.

Thermocycling experiments

[0785] Suspensions of approximately 6 mg of Embodiment I were prepared in 10 solvents at room temperature. Suspensions were cycled between 5°C and 50°C. At the end of the thermocycling, the solids were separated by centrifugation and dried under ambient conditions and under vacuum (5 mbar) before being analyzed by HT-XRPD. Subsequently, all the solids were exposed to AAC for two days and again analyzed by HT-XRPD. Thermocycling experiments usually promote the formation of the most stable polymorphic form. With the exception of the cyclohexanone experiment, all vials contained solids after thermoprofiling. The cyclohexanone solution was slowly evaporated under a gentle vacuum. The elements of embodiments 1,3 or mixtures of them were mainly identified in the wet solids. On drying these solids, conversion to Embodiment I was observed. Embodiments 3b and 3e were obtained by thermocycling in 300 pL of cyclohexanone at a concentration of 51 mg/mL (3b), and in 400 pL of isobutanol. at a concentration of 37.3 mg/ml (3e). Embodiment 5 was obtained by thermocycling in 800 pL of chloroform at a concentration of 18.6 mg/mL.

[0786] Figures 3, 4 and 5 show an overlay of HT-XRPD patterns for the embodiments listed in Table 2 and also referenced in the scans described above.

[0787] Embodiment Is was recovered from most crystallization experiments. It is a channel hydrate that has a variable number of water molecules and/or other solvents incorporated depending on environmental conditions. Conversion to embodiment 1a was observed. This form contained slightly more water (1.3 water molecules). All isostructural elements of Embodiment 1 converted to Embodiment 1 a after exposure to 40°C and 75% RH for two days. The changes of some diffraction peaks in the XRPD patterns for the elements of embodiment 1 could be attributed to the different solvent or water molecules that were incorporated into the crystal lattice. The FIG. 4 shows an overlay of HT-XRPD patterns for elements of embodiment 1. The diffractogram Is corresponds to compound Ex. 1 as starting material in embodiment Is. The diffractogram 1a corresponds to embodiment 1a which is obtained after exposure to AAC of several samples of embodiment Is. Diffractogram 1b corresponds to embodiment 1b which was obtained from the solvent equilibration experiment at room temperature in toluene. Diffractogram 1c corresponds to embodiment 1c which was obtained from the ml-scale cooling crystallization experiment in ethyl acetate/1,4-dioxane (50/50, v/v). Diffractogram 1c corresponds to embodiment 1d which was obtained from the ml-scale cooling crystallization experiment in acetonitrile/chloroform (50/50, v/v). Diffractogram 1e corresponds to embodiment 1e which was obtained from the ml-scale cooling crystallization experiment in ethyl acetate/1,4-dioxane (50/50, v/v). The If diffractogram corresponds to the If embodiment which was obtained from the solvent equilibration experiment at room temperature in p-xylene. The 1g diffractogram corresponds to the 1g embodiment which was obtained from the solvent equilibration experiment at 50°C in anisole. The 1H diffractogram corresponds to the 1H embodiment obtained from the ml-scale cooling crystallization experiment in p-xylene.

[0788] The diffractograms for the elements of embodiment 3 are shown in FIG. 5. The changes observed in the different HTXRPD patterns are probably attributed to the different solvent molecules that were incorporated into the crystal lattice. Embodiment 3 was obtained by heating Embodiment 2 at 40°C at 70% RH for 4 days. Embodiments 3b to 3e were solvated forms containing a non-stoichiometric amount of solvent that varied depending on the solvent incorporated into the crystal structure (0.3-0.7 molecules). Mixtures containing elements of embodiment 3 were unstable upon exposure to AAC and transformed in some cases to embodiment 1a or mixtures of embodiments 1a and 3e. The conversion to Embodiment 1a is attributed to the exchange of solvent molecules for water molecules upon exposure to high relative humidity and recrystallization in hydrated Embodiment 1a.

[0789] Embodiment 9 was obtained by heating Embodiment 2 to a temperature of about 200 °C followed by cooling to 25 °C and also by cyclic DSC 25-200-25-300 °C.

[0790] Embodiment 8 was obtained by heating Embodiment 5 to a temperature of about 175°C.

[0791] Embodiments of this invention include compound Ex. 1 in at least one of the forms Is, la, 1b, 1c, 1d, 1e, If, 1g, 1h, 2, 3b, 3c, 3d, 3e , 5,6,7, 8, 9 and 10. Embodiments of this invention include compounds according to this invention in the form of pharmaceutically acceptable cocrystals.

Enzyme inhibition assay

Materials

[0792] Substrate (NH2-KGGEEEEYFELVKK-CO2), internal standard peptide (NH2-SWGAIETDKEYYTVKD-CO2), and product peptide (for standard curve only) (NH2-KGGEEEEY-Pi-FELVKK-CO2), were purchased from AnaSpec (Fremont, CA, USA). JAK1-JH1JH2 (574-1154 with a His-GST tag and a C-terminal tev (ENLYFQ-G) cleavage site), JAK ³ -JH ¹ JH ² (512-1124 with a GST tag and a C-terminal tev (ENLYFQ-G) cleavage site) and TyK2-JH2JH1 (8H_tev_580-1 182-C936A-C1142A with a C-terminal tev cleavage site (ENLYFQ-G)) were purified internally. JAK2-JH1JH2 (532-1132 with a GST tag and a C-terminal tev cleavage site (ENLYFQ-G), was purchased from Invitrogen. LC/MS grade acetonitrile (ACN) and water was purchased from HoneyWell, Burdick & Jackson (Muskegon, MI, USA) 99.8% Dimethyl Sulfoxide (DMSO) and 99.5% Trifluoroacetic Acid (TFA) were purchased from EMD Chemical (Gibbstown, NJ, USA) Adenosine triphosphate (ATP), 4-morpholinopropanesulfonic acid (MOPS), magnesium chloride (MgCL), ethylenediaminetetraacetic acid (EDTA), dithiothreitol (DTT), formic acid >95% (FA) and Tween-20 were purchased from Sigma (St. Louis, MO, USA) 384-well polypropylene plates, catalog #781280 from Greiner (Monroe, NC), RapidFireTM column, AC ⁴ cartridge (Agilent Technologies , Santa Clara, CA).

[0793] HTMS experiments were performed in positive ionization mode on a RapidFire 300 instrument (Agilent Technologies, Santa Clara, CA), in conjunction with an ABSiex QTrap 4000 system with an electrospray ionization source (RF-MS) (Concord, ON, Canada). The RapidFire system was run with 3 Agilent 1200 series isocratic pumps from Agilent Technologies (Santa Clara, CA) and one ISM832C model peristaltic pump from Ismatec (Wertheim, Germany). The entire system was run using RapidFire software interfaced with Analyst software for the mass spectrometer.

test protocol

[0794] Dosing series of 11 points were performed for each compound by serially diluting 1:3 or 1:4 in DMSO, point 12 being a DMSO control. From the serial dilution plates, the sample was transferred to a 384-well assay plate (#781280, Greiner, Monroe, NC) using Labcyte Echo (Sunnyvale, CA) or Biosero ATS (San Diego, ^cA ). . Compounds were tested in duplicate. Column 12 was used for positive controls and column 24 contained negative controls with no added enzyme. A compound from our internal collection, with inhibitory activity against JAK isoforms, was used as reference compound. The final concentration of DMSO was <0.25% in a 20 pl reaction. The assay conditions for each of the proteins are summarized in Table 3. The enzymatic reaction was started by adding 10 µl of a 2x enzyme-ATP mixture to 10 µl of a 2x substrate solution prepared in reaction buffer. (50 mM Mo PS pH 7.5, 10 mM MgCl ² , 1 mM EDTA, 2 mM DTT, 0.002% Tween-20). The TyK2 enzyme was preincubated with 2 mM ATP for 30 min before the start of the reaction. Immediately after the addition of the enzyme to the reaction mixture, the plate was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 45 minutes for JAK 3 and 90 minutes for JAK1, JAK2, and TyK2. The reaction was quenched by the addition of 20 ul of 0.5% TFA containing 0.15 pM internal standard peptide using a Multidrop Combi reagent dispenser (Thermo Scientific, Waltham, MA). Typically several wells in column 24 were used for the product standard curve. After quenching, the assay plate was centrifuged at 3000 rpm for 3 minutes and sealed with pierceable aluminum foil (cat# 06644-001, Agilent) using a PlateLoc (Agilent Technologies, Santa Clara, CA). The plates were then transferred to the RapidFire for MS analysis. The inhibition of the compound was evaluated by a decrease in the levels of phosphorylated product in the sample wells compared to the uninhibited enzymatic reaction. The test conditions for the above tests are shown in Table 3 and the results of Ex. 1 209 as tested in these tests are shown in Table 4.

Table 3. Assay conditions for JAK+ family enzyme assays

High performance mass spectrometry method

[0795] Sample analysis in the RapidFire was performed using a mobile phase A consisting of water/TFA/FA (100:0.01:0.1, v/v/v), a mobile phase B consisting of in ACN/Water/TFA/FA (80:20:0.01:0.1, v/v/v). The following run parameters were used: state 1 (aspirated), 250 ms; state 2 (charge/wash), 3000 ms; state 3 (eluted), 4000 ms; state 4 (reequilibration), 1000 ms with a flow rate of 1.25 mL/min. Samples were aspirated directly from the 384 assay plate and placed on a RF-MS microscale solid phase C4 extraction cartridge (Type A). Unwanted component such as salt, cofactor, detergent and large protein were washed away and retained analytes (substrate, product and IS) were co-eluted directly on the ABSiex Qtrap 4000 system. Quantitation of peptide (substrate), phosphopeptide (product) and internal standard peptide (IS) was performed by MRM using the transitions 562^136.0, 589.2^7215.7, and 953.2^158.8 (or 974.2^158.8) respectively .

Table 4. Results of enzyme inhibition assays.

(Continuation)

(Continuation)

(Continuation)

cell assays

Cellular IL-2 pSTAT5 (JAK1/JAK3) Assay

[0796] The AlphaLISA assay (based on PerkinElmer's Alpha Technology) was performed by first plating freshly thawed PBMC (Biological Specialty Corporation) in 384-well plates. Plate at 30,000 cells per 4 pL per well in HBSS (Hanks Balanced Salt Solution) containing 0.1% protease-free IgG (immunoglobulin G)-free BSA (Jackson ImmunoResearch Cat. No. 001 -000-161). Cells were then treated with 2 pL/well of compounds diluted in DMSO to half-log titrated concentrations, with a maximum assay concentration of 10 pm and a final DMSO concentration of 0.5%, for thirty minutes at 37 °C Cells were then stimulated with 2 pL/well IL-2 (R&D Systems Cat. No. 202-IL-050) at 5 ng/ml for thirty minutes at 37°C. Cell reactions were terminated by the addition of 2 pL/well lysis buffer (PerkinElmer Cat. No. ALSU-PST5-A10K) followed by a five minute incubation at room temperature. 5 µL/well of acceptor mix (PerkinElmer Cat. No. ALSU-PST5-A10K) was added to the cells and incubated in the dark for one hour at room temperature. Next, 5 µL/well of donor mix (PerkinElmer Cat. No. ALSU-PST5-AIOK) was added to the cells and incubated in the dark overnight at room temperature. Finally, the plates were read on a PerkinElmer EnVision for detection of the time-resolved fluorescence signal. Percent IL-2 dependent pSTAT5 inhibition was determined at test concentrations of compound; and for each compound a dose curve was generated and the IC ⁵⁰ was calculated. Compound IC ⁵⁰ was calculated by non-linear regression, sigmoidal dose-response analysis of the titration curve of half-log dilution of compound concentration vs. alpha signal. The acronym "Alpha" stands for Amplified Luminescent Proximity Homogeneous Assay; the Alpha signal is a luminescent/fluorescent signal.

pSTAT4 IFNa Cell Assay (JAK1/TYK2)

[0797] The AlphaLISA assay (based on PerkinElmer's Alpha Technology) was first performed by seeding fresh thawed PBMC plates (Biological Specialty Corporation) into 384-well plates at 100,000 cells per 6 µl per well in DMEM (Dulbecco's Modified Eagle's Medium) which contains 10% FBS (fetal bovine serum) and 1000 IU/ml penicillin and 1,000 mg/ml streptomycin. Cells were then treated with 2 pL/well of compounds diluted in DMSO at half-log titrated concentrations, with a maximum assay concentration of 10 pM and a final DMSO concentration of 0.5%, for thirty minutes at 37 °C Cells were then stimulated with 2 pL/well IFNα (PBL Assay Science Cat. No. 11101-2) at 4 ng/ml for thirty minutes at 37°C. Cell reactions were terminated by the addition of 2 pL/well lysis buffer (PerkinElmer Cat. No. ALSU-PST4-A10K) followed by a five minute incubation at room temperature. 4 µL/well acceptor mix (PerkinElmer Cat. No. ALSU-PST4-A10K) was added to the cells and incubated in the dark for one hour at room temperature. Next, 4 pL/well of the donor mix (PerkinElmer Cat. No. ALSU-PST4-A10K) was added to the cells and incubated in the dark overnight at room temperature. Finally, the plates were read on a PerkinElmer EnVision for detection of the time-resolved fluorescence signal. Percent IFNa-dependent inhibition of pSTAT4 was determined at test concentrations of compound; and for each compound a dose curve was generated and the IC ⁵⁰ was calculated. Compound IC ⁵⁰ was calculated by non-linear regression, sigmoidal dose-response analysis of the titration curve of half-log dilution of compound concentration vs. alpha signal. The term "Alpha" is defined in the description of the cell assay immediately above.

GM-CSF pSTAT5 Cell Assay (JAK2/JAK2)

[0798] The AlphaLISA assay (based on PerkinElmer's Alpha Technology) was performed by first plating freshly thawed PBMC (Biological Specialty Corporation) in 384-well plates at 30,000 cells per 4 mL per well in HBSS containing 0.1% free BSA protease and without IgG (Jackson ImmunoResearch Cat. No. 001-000-161). Cells were then treated with 2 pL/well of compounds diluted in DMSO to half-log titrated concentrations, with a higher test concentration of 10 pM and a final DMSO concentration of 0.5%, for thirty minutes at 37°C. Cells were then stimulated with 2 pL/well of GMCSF (R&D Systems Cat. No. 215-GM-050) at 11 pg/ml for fifteen minutes at 37°C. Cell reactions were terminated by the addition of 2 pL/well lysis buffer (PerkinElmer Cat. No. ALSU-PST5-A10K) followed by a five minute incubation at room temperature. 5 µL/well of acceptor mix (PerkinElmer Cat. No. ALSU-PST5-A10K) was added to the cells and incubated in the dark for one hour at room temperature. Next, 5 pL/well of donor mix (PerkinElmer Cat. No. ALSU-PST5-A10K) was added to the cells and incubated in the dark overnight at room temperature. Finally, the plates were read on a PerkinElmer EnVision for detection of the time-resolved fluorescence signal. Percent GMCSF-dependent inhibition of pSTAT5 was determined at test concentrations of compound; and for each compound a dose curve was generated and the IC ⁵⁰ was calculated. Compound IC ⁵⁰ was calculated by non-linear regression, sigmoidal dose-response analysis of the titration curve of half-log dilution of compound concentration vs. alpha signal. The term "Alpha" is defined in the description of the cellular IL-2 pSTAT5 (JAK1/JAK3) assay. Examples 1-5, 10, 22, 34, 38, 55, 74 and 85 were tested in this cell assay and the results are shown in Table 5.

Table 5. Data from cell-based assays

[0799] Examples 1-5, 10, 22, 34, 38, 55, 74 and 85 were tested in solubility and permeability tests. The results of the solubility based test are presented in Table 6 entitled Solubility Test Data and results of the permeability test are presented in Table 7 entitled MDCK-MDR1 Permeability Data. These solubility and permeability tests are described below under the headings Solubility Tests and Permeability Tests, respectively.

solubility tests

[0800] Solubility measurements were performed in the following solubility media: simulated gastric fluids (34.2 mM sodium chloride and 100 mM hydrochloric acid) or simulated intestinal fluids (fasting state [pH 6.5]: 3 mM sodium taurocholate, 0.75 mM lecithin, 28.4 mM monobasic sodium phosphate, 8.7 mM sodium hydroxide, and 105.9 mM sodium chloride). Test compounds were dissolved in DMSO at a concentration of 10 mM. Test compounds were dispensed (20 ul) into Nunc 1-ml-96-Deep-Well-PP plates, and DMSO was evaporated by nitrogen purge from a TurboVap 96 for 6 hours or until a dry residue was produced. . Next, 400 ul of solubility medium was added to the well containing the dried solid. A pre-cut well cap was securely placed on top of the well plate block and the samples were shaken vigorously for 2-5 days at room temperature. After the incubation period, samples were filtered through an AcroPrep 1-ml-96-Filter plate into a fresh 2-ml-96-Deep-Well-PP plate, and supernatants quantified by UV-HPLC using a 3-point filter. calibration ranging from 0.004 to 0.55 mM. The solubility of each compound was calculated from the following equation:

Solubility = ________ Sample Peak Area _____

Mean response factor for 3 standards

Solubility values were in the range of 4 - 400 |uM. Values outside this range were reported as < 4 |uM or > 400 |uM. Solubilities are reported as long as the test compound was stable enough to complete the corresponding solubility determination.

Table 6. Data from the solubility test

permeability tests

[0801] Permeability measurements were performed according to the Cyprotex protocol using the MDCK-MDR1 cell line obtained from the NIH (Rockville, MD, USA). Cells between passage numbers 6-30 were plated on a Multiscreen plate™ (Millipore) at a cell density of 3.4 X 105 cells/cm2 and cultured for three days prior to permeability studies. The cells in this assay form a cohesive sheet of a single cell layer filling the surface area of the culture dish, also known as a confluent monolayer, and on the fourth day test compound was added to the apical side of the membrane. and the transport of the compound through the monolayer was monitored for a period of 60 min.

[0802] In a simple and basic way of introducing the terms "A" and "B" that are often used in these assays, the apical ("A") side or compartment of an entity is the side of said entity that is exposed to the external lumen or environment, while the basolateral ("B") side or compartment is the side or compartment of said entity that is exposed to the typically internal environment, encompassing the opposite side. For example, when said entity is illustratively a cell of the intestinal epithelium, the apical side of said intestinal cell would be the side of the cell exposed to the intestinal lumen, while the basolateral side would be the side that is exposed to the blood.

[0803] Test compounds were dissolved in DMSO at a concentration of 10 mM. Dosing solutions were prepared by diluting test compound with assay buffer (Hanks balanced salt solution), pH 7.4, to a final concentration of 5 pM. To assess apical to basolateral ("AB") permeability, the buffer was removed from the apical part and replaced with a test compound dosing solution with or without the permeability glycoprotein inhibitor ("PgP", "P- gP", "Pgp" or "Pgp") elacridar (2 pM). For assessment of basolateral to apical ("BA") patency, the buffer from the companion plate was removed and replaced with test compound dosing solution. The incubations were carried out in duplicate at 37 °C in an atmosphere of 5% CO ² with a relative humidity of 95%. Each trial included the reference markers propranolol (high permeability) and prazosin (PgP substrate). After a 60 minute incubation, the apical and basolateral samples were diluted and test compounds quantitated by LC/MS/MS using an 8-point calibration in the range of 0.0039 to 3 pM with the appropriate dilution of samples. samples (recipient dilution factor = 1; donor dilution factor). and Co dilution factor = 10). The permeability coefficient (Papp) for each compound was calculated from the following equation: Papp = (dQ/dt) / (Co x S), where dQ/dt is the drug permeation rate through cells, Co is the concentration of the donor compartment at time zero, and S is the area of the cell monolayer.

[0804] Percent recovery was measured for all incubation conditions. These measurements did not reveal unacceptable compound/plaque binding or compound accumulation in the cell monolayer.

[0805] The second and third columns in Table 7 show the Papp(A-B) values for apical to basolateral compound transport without (second column) and with a P-gp inhibitor (third column, denoted as Peapp( A-B)) that was elacridar. Papp(A-B) gives an indication of the degree of permeation through cells in this assay, which is intended to model transcellular transport through Pgp-expressing cells, such as Pgp-expressing cells of the gastrointestinal tract. The Peapp(A-B) values (Papp(A-B) in the presence of P-gp inhibitor) given in column 3 are determined to confirm the role of P-gp in compound efflux. The fourth column of Table 7 shows the Papp(B-A) values for basolateral to apical compound transport. The test compound efflux ratios are given in the fifth column of Table 7 as Papp(B-A)/Papp(A-B) using the corresponding coefficient of permeability values from the fourth and second columns in the same table. The efflux ratios (fifth column, Table 7) are consistently greater than 2 for compounds (A)-(C) and also for compounds Ex. 1 -5, 10, 22, 34, 38, 55, 74 and 85, indicating that compound output occurs for all of these compounds.

[0806] Papp values (A-B) in column 2 are generally low and comparable for reference compounds (A)-(C) and also for compounds Ex. 1-5, 10, 22, 34, 38, 55, 74 and 85. These low values indicate low permeability for all of these compounds, which is due to P-gp effects, since all of these compounds are P-gp substrates as indicated. by the values given in column 5 all being greater than 2. To be characterized as low permeability, the values given in the third and fourth columns for P e app(A-B) and Papp(B-A), respectively, must be low. However, these data show that the Papp(B-A) values for compounds (A)-(C) are higher than the corresponding values for compounds Ex. 1-5, 10, 22, 34, 38, 55, 74 and 85.

[0807] The integrity of each monolayer was monitored by examining the penetration of lucifer yellow by fluorimetric analysis. This examination revealed that the cells in this assay maintained a satisfactory confluent monolayer.

Table 7. MDCK-MDR1 permeability data.

in vivo studies

Oral Dosage - Protocol 1

[0808] Three non-fasting female C57BL/6 mice were orally administered test compound at a dose of 25 mg/kg p.o. as a solution in 20% beta-hydroxypropyl. cyclodextrin (HPpCD) at a dose volume of 5 ml/kg. Blood samples were collected at 0.5, 2, and 4 h post-dose by retroorbital bleeding or venipuncture from the dorsal metatarsal vein. Blood samples were collected in tubes containing anticoagulant (heparin-Na) and placed on wet ice. The plasma fraction was separated by centrifugation and frozen at -20 °C for up to 4 h and at -80 °C after 4 h, unless analyzed shortly after sample collection. Colon samples were collected 4 h post-dose. From the beginning of the cecum, a 4-6 cm colon sample was dissected, cut open along the longitudinal axis, and the solid contents removed by washing with 2 ml of saline. The colon was further lavaged by placing it in 5 ml of saline and agitated for 5 seconds. The colon sample was then dried, weighed and homogenized as 1 part tissue (g) to 4 parts HPLC grade water (ml). Compound concentrations in plasma and colonic homogenate were determined using a qualified liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) method. This protocol was used to evaluate the following test compounds: Compounds (B) and (C) and Examples 10 and 74. Oral Dosing Protocol 2

[0809] Three non-fasting female C57BL/6 mice were orally administered test compound at a dose of 25 mg/kg p.o. as a solution in 20% HPpCD in a dose volume of 5 mL/kg. Blood samples were collected at 0.5, 2, and 4 h post-dose via retroorbital hemorrhage or dorsal metatarsal vein. Blood samples were collected in tubes containing anticoagulant (Heparin-Na) and placed on wet ice. The plasma fraction was separated by centrifugation and frozen at -20 °C for up to 4 h and at -80 °C after 4 h, unless analyzed soon after sample collection. Colon samples were collected 4 h post-dose. From 2 cm below the cecum, a 4 cm sample of the colon was dissected, cut open along the longitudinal axis and the solid contents removed by washing with 2 ml of saline. The colon was further lavaged by placing it in 5 ml of saline and agitated for 5 seconds. The colon sample was then dried, weighed and homogenized as 1 part tissue (g) to 4 parts HPLC grade water (ml). Concentrations of the compound in plasma and colonic homogenate were determined using a qualified method of liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS). This protocol was used to evaluate the following test compounds: Compound (A) and Examples 1-5, 22, 34, 38, 55 and 85.

Dosage IC-Protocol 3

[0810] Intracolonic (IC) Dose Group: Following isoflurane inhalation anesthesia, three non-fasting female C57BL/6 mice were administered the compound intracolonically through a small incision in the abdominal wall using syringe and needle at a dose of 5 mg/kg as a solution in 20% HPpCD at a dose volume of 1 ml/kg. Blood samples were collected at 0.5, 2, and 4 h post-dose by retroorbital bleeding. Blood samples were collected in tubes containing anticoagulant (heparin-Na) and placed on wet ice.

The plasma fraction was separated by centrifugation and frozen at -20 °C for up to 4 h and at -80 °C after 4 h, unless analyzed soon after sample collection. Colon samples were collected 4 h post-dose. From 2 cm below the cecum, a 4 cm sample of the colon was dissected, cut open along the longitudinal axis and the solid contents removed by washing with 2 ml of saline. The colon was further lavaged by placing it in 5 ml of saline and agitated for 5 seconds. The colon sample was then dried, weighed and homogenized as 1 part tissue (g) to 4 parts HPLC grade water (ml). Concentrations of the compound in plasma and colonic homogenate were determined using a qualified method of liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS). This protocol was used to evaluate the IC dosing of the following test compounds: Examples 1, 3 and 4.

[0811] Compounds eg. 1-5, 10, 22, 34, 38, 55, 74, and 85 are further characterized by the physicochemical properties provided in Table 8. cLogP and tPSA values were calculated using ChemBioDraw Ultra 14.0, where P is the n -octanol - water partition coefficient. The topological polar surface area (tPSA) is calculated as the sum of the surface area of all polar atoms, mainly oxygen and nitrogen, including also their bound hydrogens.

Table 8. Some physicochemical properties of the compounds Ex. 1-5, 10, 22, 34, 38, 55, 74 and 85

Claims (2)

1. A compound or a pharmaceutically acceptable salt thereof, selected from 2-cyano-N-((1-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)methyl)ethanesulfonamide; 2-(1-((1 r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (pyrimidin-4-ylmethyl)acetamide; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 3-hydroxy-2,2-dimethylpropyl)acetamide; N-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-2-(1 -((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d ]pyrrolo[2,3-b]pyridin-2-yl)acetamide; 2-(1 -((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (((1S,3R,5R,7S)-3-hydroxyadamantan-1-yl)methyl)acetamide; N-(2-cyano-2-methylpropyl)-2-(1-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-2-yl)acetamide; N-(4-cyanobicyclo[2,2,1]heptan-1-yl)-2-(1-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5 -d]pyrrolo[2,3-b]pyridin-2-yl)acetamide; 2-(1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 3-hydroxyoxetan-3-yl)methyl)acetamide; 2-((7r,49-4-(2-(2-(4-morpholinopiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1( 6H)-yl)cyclohexyl)acetonitrile; 2-(1 -((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1 r,4r)-4-(hydroxymethyl)cyclohexyl)acetamide; 2-(1-(( 4r,4í^-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-hydroxyethyl)acetamide; N-((1-((fr,4rf-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzimidamide; 2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 1-hydroxycyclobutyl)methyl)acetamide; 2-(1-((fr,4r,)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (pyrazin-2-ylmethyl)acetamide; N-((1 H-imidazol-2-yl)methyl)-2-(1-((fr,4rf-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-2-yl)acetamide; 2-(1 -((fr,4rf-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 1 R,3R)-3-hydroxycyclobutyl1 )acetamide; 2-(1 -((fr,4rf-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(1 -methyl-1Hpyrazol-4-yl)acetamide; 2-(1 -((fr,4rf-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 1 S,4S)-4-hydroxycyclohexyl)acetamide; 2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 1 s,3r,5R,7S)-3-hydroxyadamantan-1-yl)acetamide; N-(4-(cyanomethyl)bicyclo[2,2,1]heptan-1-yl)-2-(1-((fr,4rf-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4, 5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide; 2-(1-((fr,4r,)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (3-hydroxy-3-methylbutyl)acetamide; 2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(1 -isobutylpiperidin-4-yl)acetamide; 2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(1 H-pyrazol-4-yl)acetamide; 2-(1-((fr,4r,)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (4-(hydroxymethyl)benzyl)acetamide; 2-((7r,49-4-(2-(2-(4-(Hydroxymethyl)piperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine -1(6H)-yl)cyclohexyl)acetonitrile; 2-(1 -((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1 H-pyrazol-3-yl)acetamide; 2-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(( 1-hydroxycyclopropyl)methyl)acetamide; 2-((7r,49-4-(2-(2-(4-(2-Hydroxypropan-2-yl)piperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile; 2-(1 -((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)acetamide; N-((1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-hydroxy -3-methylbutanamide; 2-(1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2 -methoxyethyl)acetamide; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-8-fluoro-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide; 2-((1r,4r)-4-(2-(1-(Methylsulfonyl)azetidin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl )cyclohexyl)acetonitrile; 3- Cyano-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)propanamide; 3-(3-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)azetidine -1-yl)-3-oxopropanenitrile; 2-((1r,4r)-4-(2-(1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin- 1(6H)-yl)cyclohexyl)acetonitrile; 2-(8-chloro-1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide; 2-(8-bromo-1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) -N-(2-hydroxy-2-methylpropyl)acetamide; 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-methylacetamide ; and 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (4-cyanophenyl)acetamide. 2. A compound selected from 2-cyano-N-((1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl )methyl)ethanesulfonamide; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( pyrimidin-4-ylmethyl)acetamide; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 3-hydroxy-2,2-dimethylpropyl)acetamide; N-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-2-(1 -((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo [2,3-b]pyridin-2-yl)acetamide; 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( ((1S,3R,5R,7S)-3-hydroxyadamantan-1-yl)methyl)acetamide; N-(2-cyano-2-methylpropyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)acetamide; N-(4-cyanobicyclo[2,2,1]heptan-1-yl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)acetamide; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (3-hydroxyoxetan-3-yl)methyl)acetamide; 2-((1r,4r)-4-(2-(2-(4-morpholinopiperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile; 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( ( 1r,4r)-4- (hydroxymethyl)cyclohexyl)acetamide; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 2-hydroxyethyl)acetamide; N-((1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)benzimidamide ; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1-hydroxycyclobutyl)methyl)acetamide; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( pyrazin-2-ylmethyl)acetamide; N-((1 H-imidazol-2-yl)methyl)-2-(1-((1 r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo [2,3-b]pyridin-2-yl)acetamide; 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1R,3R)-3-hydroxycyclobutyl)acetamide; 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1-methyl-1Hpyrazol-4-yl)acetamide; 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1S,4S)-4-hydroxycyclohexyl)acetamide; 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( (1 s,3r,5R,7S)-3-hydroxyadamantan-1-yl)acetamide; N-(4-(cyanomethyl)bicyclo[2,2,1]heptan-1-yl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4 ,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide; 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 3-hydroxy-3-methylbutyl)acetamide; 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1-isobutylpiperidin-4-yl)acetamide; 2-(1 -((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1 H-pyrazol-4-yl)acetamide; 2-(1-((1r,4fi)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(hydroxymethyl)benzyl)acetamide; 2-((7r,4rM-(2-(2-(4-(Hydroxymethyl)piperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile; 2-(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 1H-pyrazol-3-yl)acetamide; 2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-((1- hydroxycyclopropyl)methyl)acetamide; 2-((ir,4r1-4-(2-(2-(4-(2-Hydroxypropan-2-yl)piperidin-1-yl)-2-oxoethyl)imidazo[4,5-d]pyrrolo[2 ,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile; 2-(1-((7r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-( 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)acetamide; N-((1-((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)-3 -hydroxy-3-methylbutanamide; 2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-methoxyethyl )acetamide; 2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-8-fluoro-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (2-hydroxy-2-methylpropyl)acetamide; 2-((ir,4r1-4-(2-(1-(Methylsulfonyl)azetidin-3-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) cyclohexyl)acetonitrile;3- cyano-N-((1-((ir,4r1-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)methyl)propanamide; 3-(3-(1 -((7r,4r,M-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)azetidine- 1-yl)-3-oxopropanenitrile; 2-((ir,4r1-4-(2-(1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1 (6H)-yl)cyclohexyl)acetonitrile; 2-(8-chloro-1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (2-hydroxy-2-methylpropyl)acetamide; 2-(8-bromo-1-((7r,4rM-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N- (2-hydroxy-2-methylpropyl)acetamide; 2-(1-((7r,4rM-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-methylacetamide; 2- (1-((ir,4r1-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(4-cyanophenyl )acetamide; and pharmaceutically acceptable cocrystals thereof.